Treatment of metabolic disorders in equine animals

ABSTRACT

One or more SGLT2 inhibitors or pharmaceutically acceptable forms thereof are provided for use in the treatment and/or prevention of a metabolic disorder of an equine animal. For example, the treatment and/or prevention can be for laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndrome in an equine animal.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/672,705, filed Mar. 30, 2015, which claims priority from EP14162983.2, filed Apr. 1, 2014, and from EP 14176714.5, filed Jul. 11,2014, and from EP 14187223.4, filed Oct. 1, 2014, the disclosures ofwhich are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to veterinary medicine, in particular tothe treatment and/or prevention of metabolic disorders in equineanimals.

BACKGROUND OF THE INVENTION

Equine animals, e.g., horses, are affected by various metabolicdisorders, including insulin resistance and hyperinsulinaemia. Suchinsulin-related disorders in equine animals, for example, are onlyrarely associated with diabetes mellitus and hyperglycemia, as it is inhumans or various other mammals. However, in equine animals, insulinalso regulates vital metabolic functions; e.g., insulin drives glucoseinto tissues such as liver, adipose, and skeletal muscle; inducesvasoconstrictive and vasodilatory pathways; and regulates protein andfat metabolism. Insulin-related disorders thus have a severe andlife-threatening impact on the health of equine animals. They arecorrelated or may be associated with a number of further equinedisorders, conditions or syndromes, including impaired glucosetolerance, dyslipidemia, dysadipokinemia, obesity and/or regionaladiposity, subclinical inflammation or systemic inflammation, inparticular low grade systemic inflammation, which also comprises adiposetissue, Equine Metabolic Syndrome (EMS) and/or Equine Pituitary ParsIntermedia Dysfunction (PPID), also known as equine Cushing's syndrome,which are characterized e.g. by laminitis, vascular dysfunction,hypertension, hepatic lipidosis, hyperadrenocorticism and/oratherosclerosis.

In particular, insulin resistance in equine animals may be associatedwith EMS and/or PPID or may cause the development or progression ofPPID. EMS and/or PPID may become manifest e.g., in laminitis. Thisdevastating worldwide cause of mortality in horses is a multifactorialcondition causing structural and mechanical changes in the supportingtissues within the hoof, resulting in acute and chronic pain, lameness,and potentially euthanasia. Equine laminae are highly metabolicallyactive, and a complex microvascular bed is present. A significant bodyof evidence exists also for vascular dysfunction (endothelial celldysfunction) during equine laminitis (ref 1: Katz & Bailey, 2012). Invitro studies in equine digital vessels have shown insulin resistancemediated endothelial and/or vascular dysfunction (ref. 2: Venugopal etal., 2011). A direct link between hyperinsulinaemia and laminitis hasbeen documented in naturally-occurring forms of the disease (ref. 3:Treiber et al., 2006). However, the mechanism by which insulinresistance and/or hyperinsulinemia cause EMS and/or PPID, in particularvascular dysfunction and/or laminitis in horses is poorly understood.

No satisfactory treatment is currently available for metabolic disorderssuch as insulin resistance, hyperinsulinaemia and associated disordersin equine animals, such as EMS and/or in case they are associated withor secondary to e.g., PPID, which become manifested e.g., by laminitis,vascular dysfunction, hypertension in equine animals. For instance, theuse of Metformin is controversially discussed (ref 4: Tinworth et al.,2012). Similarly, treatment of equine PPID with pergolide seems tohardly affect insulin resistance and/or hyperinsulinemia (ref 5: Gehlen,2014).

In human medicine, insulin resistance, e.g., when manifested as diabetesmellitus type 2, is a well-recognized condition, and may lead inparticular to hyperglycemia (pathologically increased plasma glucoselevels). Several oral antihyperglycemic drugs are approved for humandiabetes. These drugs act, e.g., by stimulating pancreatic insulinsecretion in a glucose-independent or glucose-dependent manner(sulfonylurea/meglitinides, or DPP IV inhibitors, respectively), byenhancing tissue sensitivity to insulin (biguanides,thiazolidinediones), or by slowing postprandial intestinal glucoseabsorption (alpha-glucosidase inhibitors).

Other antihyperglycemic approaches have been contemplated for treatingdiabetes and high blood sugar, including inhibition of the renalsodium-dependent glucose cotransporter SGLT2. SGLT2 in the kidneyregulates glucose levels by mediating the reabsorption of glucose backinto the plasma following filtration of the blood. SGLT2 inhibition thusinduces glucosuria or glycosuria and may reduce blood glucose levels.

SGLT2 inhibition has not previously been contemplated for use in equineanimals, in particular in insulin-resistant equine animals. In equineanimals, insulin-resistance, i.e., failure of tissues to respondappropriately to insulin, generally becomes manifested ashyperinsulinemia. When insulin-resistant target tissues, e.g., skeletalmuscle, have a reduced capacity for glucose uptake, the pancreas isstimulated to release more insulin, leading to hyperinsulinaemia.However, unlike in humans, e.g., insulin resistance in equine animals,e.g., horses, is generally not associated with hyperglycemia (ref. 6:Frank et al., 2011). Insulin-resistant equine animals, e.g., horses, donot appear to have high blood glucose. For that reason, it would appearto be counter-intuitive to apply an approach that reduces blood glucoseby transferring glucose out of the blood into the urine, even if thiswas previously known in a context of high blood glucose.

DISCLOSURE OF THE INVENTION Summary of the Invention

The present invention has surprisingly found that inhibition of SGLT2 iseffective and safe in the treatment and/or prevention of metabolicdisorders in equine animals. The present invention thus provides the useof one or more SGLT2 inhibitors or pharmaceutically acceptable formsthereof in the treatment and/or prevention of a metabolic disorder of anequine animal. Further aspects of the invention are defined below, aswell as in the claims.

According to the invention, the metabolic disorder may be insulinresistance, hyperinsulinemia, and/or a clinical condition/signassociated with insulin resistance and/or hyperinsulinemia.

The metabolic disorder, or said clinical condition/sign associated withinsulin resistance and/or hyperinsulinemia, may be one or more disorderselected from insulin resistance, hyperinsulinemia, impaired glucosetolerance, dyslipidemia, dysadipokinemia, subclinical inflammation,systemic inflammation, low grade systemic inflammation, which alsocomprises adipose tissue, obesity, regional adiposity, laminitis,vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis,hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction and/orEquine Metabolic Syndrome.

According to the invention, the equine animal may be suffering from oneor more of impaired glucose tolerance, dyslipidemia, dysadipokinemia,subclinical inflammation, systemic inflammation, low grade systemicinflammation, which also comprises adipose tissue, obesity, regionaladiposity, laminitis, vascular dysfunction, hypertension, hepaticlipidosis, atherosclerosis, hyperadrenocorticism, Pituitary ParsIntermedia Dysfunction and/or Equine Metabolic Syndrome.

According to the invention, impaired glucose tolerance, dyslipidemia,dysadipokinemia, subclinical inflammation, systemic inflammation, lowgrade systemic inflammation, which also comprises adipose tissue,obesity, regional adiposity, laminitis, vascular dysfunction,hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism,Pituitary Pars Intermedia Dysfunction and/or Equine Metabolic Syndromemay be associated with hyperinsulinemia and/or insulin resistance.

According to the invention, the metabolic disorder may behyperinsulinemia and/or insulin resistance, and said hyperinsulinemia orinsulin resistance may optionally be associated with one or more ofimpaired glucose tolerance, dyslipidemia, dysadipokinemia, subclinicalinflammation, systemic inflammation, low grade systemic inflammation,which also comprises adipose tissue, obesity, regional adiposity,laminitis, vascular dysfunction, hypertension, hepatic lipidosis,atherosclerosis, hyperadrenocorticism, Pituitary Pars IntermediaDysfunction and/or Equine Metabolic Syndrome.

The equine animal may, e.g., be a horse. The equine animal may, e.g., bea pony. The equine animal may be obese and/or exhibit regionaladiposity. However, for instance as regards Pituitary Pars IntermediaDysfunction, the equine animal may also be not obese and/or be presentwith muscle wasting and/or exhibit hyperglycemia.

The pharmaceutically acceptable form of the one or more SGLT2 inhibitorsmay be a crystalline complex between the one or more SGLT2 inhibitorsand one or more amino acids, e.g., proline.

According to the invention, the one or more SGLT2 inhibitors orpharmaceutically acceptable forms thereof may be provided, e.g., fororal or parenteral administration, preferably for oral administration.

The one or more SGLT2 inhibitors or pharmaceutically acceptable formsthereof may be administered in dosages of 0.01 to 3.0 mg/kg body weightper day, preferably from 0.02 to 1.0 mg/kg body weight per day, morepreferably from 0.03 to 0.4 mg/kg body weight per day. Thus, the one ormore SGLT2 inhibitors or pharmaceutically acceptable forms thereof maybe prepared for the administration of 0.01 to 3.0 mg/kg body weight perday, preferably from 0.02 to 1.0 mg/kg body weight per day, morepreferably from 0.03 to 0.4 mg/kg body weight per day.

The one or more SGLT2 inhibitors or pharmaceutically acceptable formsthereof is preferably administered only once per day.

According to the present invention, any SGLT2 inhibitor orpharmaceutically acceptable form thereof may be used. In preferredembodiments, the one or more SGLT2 inhibitors are aglucopyranosyl-substituted benzene derivative. A number of SGLT2inhibitors which may be used according to the invention are described indetail below.

The present invention also provides a pharmaceutical compositioncomprising one or more SGLT2 inhibitors or a pharmaceutically acceptableform thereof, for use according to the invention as disclosed herein.

In the examples provided herein, therapeutic and prophylactic benefitsresulting from inhibition of SGLT2 according to the present inventionare demonstrated experimentally. Experimental data disclosed herein areintended to illustrate the invention, but not to have any limitingeffect upon the scope of protection, which is defined herein below bythe claims.

In particular, the present invention has surprisingly found that the useof one or more SGLT2 inhibitors according to the present inventionadvantageously leads to a reduction in insulin resistance in treated,insulin resistant equine animals. That is, equivalently, the use of oneor more SGLT2 inhibitors according to the present inventionadvantageously leads to increased insulin sensitivity in treated,insulin resistant equine animals.

The use of one or more SGLT2 inhibitors according to the presentinvention advantageously leads to reduced plasma insulin levels, i.e.,allows effective treatment of hyperinsulinemia. Thus, the use of one ormore SGLT2 inhibitors according to the present invention advantageouslyleads to reduced baseline plasma insulin levels, and/or a reducedinsulin excursion due to a glycemic challenge, e.g., as measured duringan intravenous glucose tolerance test (ivGTT), an oral sugar test (OST)or after any other form of glucose intake, e.g., after a meal(postprandial insulin excursion).

The use of one or more SGLT2 inhibitors according to the presentinvention advantageously leads to a reduction in hyperinsulinemia andsurrogate markers of insulin resistance in treated, insulin resistantequine animals.

The glucose excursion after a challenge with insulin (e.g., in anintravenous insulin tolerance test (ivITT)), or after a challenge withglucose (e.g., as measured during an intravenous glucose tolerance test(ivGTT), an oral sugar test (OST) or after any other form of glucoseintake, e.g., after a meal (postprandial glucose excursion)), or asmeasured in a combined glucose-insulin tolerance test (CGIT), of anequine animal treated in accordance with the invention is,advantageously, also improved. That is, after a challenge with insulin,the decrease in glucose levels is greater and/or more rapid; or after achallenge with glucose, the glycemic peak of the glucose excursion islowered and/or the duration of the glucose excursion is reduced.

The use of one or more SGLT2 inhibitors according to the presentinvention thus generally leads to improved (i.e., increased) glucosetolerance, i.e., equivalently, reduces glucose intolerance.

The use of one or more SGLT2 inhibitors according to the presentinvention advantageously also leads to a reduction in plasma levels ofnon-esterified fatty acids, or an improved elimination of non-esterifiedfatty acids (NEFAs) from the bloodstream e.g., after a challenge withinsulin (e.g., as measured during an intravenous insulin tolerance test(ivITT)), or after a challenge with glucose (e.g., as measured during anintravenous glucose tolerance test (ivGTT), an oral sugar test (OST) orafter any other form of glucose intake, e.g., after a meal, thatinitiates a blood insulin excursion, or as measured in a combinedglucose-insulin tolerance test (CGIT).

The use of one or more SGLT2 inhibitors according to the presentinvention advantageously also leads to a reduction in body fat andimproved adipokine profile, e.g., reduced blood leptin levels. Theinvention is also associated with anti-obesity effects, and/or lead to adecrease in body mass in an equine animal. In one aspect, the inventionthus allows obesity and/or obesity-related metabolic disorders to bemanaged in an equine animal.

The use of one or more SGLT2 inhibitors according to the presentinvention generally reduces dyslipidemia, dysadipokinemia, obesityand/or regional adiposity. Thus, the use of SGLT2 inhibitors allows forthe treatment and/or prevention of dyslipidemia, dysadipokinemia,obesity and/or regional adiposity, in particular when associated withinsulin resistance and/or hyperinsulinemia in equine animal.

Advantageously, the use of one or more SGLT2 inhibitors according to thepresent invention does not cause hypoglycemia.

The effects of the uses according to the present invention (i.e., theabove-mentioned beneficial effects upon insulin resistance/sensitivity,insulin excursion, second phase insulin secretion, glucose tolerance,elimination of non-esterified fatty acids, body fat, and/or blood leptinlevels) are also advantageous in that they allow for the prevention ofcomplications of insulin resistance and/or hyperinsulinemia, and thetreatment, prevention or control of further metabolic disorders,symptoms and/or clinical conditions/signs/signs that are associated withinsulin resistance and/or hyperinsulinemia in equine animals. They thusallow the possibility of preventing and/or delaying the onset of suchcomplications, further metabolic disorders, symptoms and/or clinicalcondition/signs in equine animals.

The use of one or more SGLT2 inhibitors according to the presentinvention also provides for treatment and/or prevention of laminitis,i.e., leads to reduction of lameness and/or time to recovery from alaminitis episode.

The use of one or more SGLT2 inhibitors according to the presentinvention provides for treatment and/or prevention of vasculardysfunction, i.e., improvement of altered digital perfusion and/orimproved vascular response to contractile or dilatatory stimuli.

The use of one or more SGLT2 inhibitors according to the presentinvention also provides for treatment and/or prevention of EquineMetabolic Syndrome (EMS).

The use of one or more SGLT2 inhibitors according to the presentinvention also provides for treatment and/or prevention of PituitaryPars Intermedia Dysfunction (PPID), for instance prevention of thedevelopment and/or progression of Pituitary Pars Intermedia Dysfunction(PPID) in an equine animal. That is the onset and/or progression ofPituitary Pars Intermedia Dysfunction (PPID) in an equine animal may befully inhibited or delayed.

The use of one or more SGLT2 inhibitors according to the presentinvention may prevent the development and/or recurrence of laminitis inan equine animal suffering from EMS and/or PPID.

The use of one or more SGLT2 inhibitors according to the presentinvention may prevent the development and/or recurrence of vasculardysfunction in an equine animal suffering from EMS and/or PPID.

The use of one or more SGLT2 inhibitors according to the presentinvention may prevent the development and/or recurrence of hypertensionin an equine animal suffering from EMS and/or PPID.

The use of one or more SGLT2 inhibitors according to the presentinvention may prevent the development and/or recurrence of hepaticlipidosis in an equine animal suffering from EMS and/or PPID.

The use of one or more SGLT2 inhibitors according to the presentinvention may prevent the development and/or recurrence of regionalobesitas in an equine animal suffering from EMS and/or PPID.

A further advantage of the present invention is that the use of SGLT2inhibitors is effective against the metabolic disorders alone, i.e., ifdesired the use of one or more SGLT2 inhibitors in an equine animalprovides a monotherapy (i.e. a stand-alone therapy; i.e., no othermedication is administered to the equine animal for the treatment orprevention of the same metabolic disorder). The invention also allowsfor the possibility for combination therapy with another drug (e.g., afurther insulin sensitizing drug).

The effects of using one or more SGLT2 inhibitors according to thepresent invention (e.g., the above-mentioned beneficial effects uponinsulin resistance/sensitivity, plasma insulin levels, insulinexcursion, glucose excursion, glucose tolerance, elimination ofnon-esterified fatty acids, body fat, and/or blood leptin levels) may berelative to the same or a comparable equine animal prior toadministration of one or more SGLT2 inhibitors according to the presentinvention, and/or relative to a comparable equine animal that has notreceived said treatment (e.g., a placebo group). In either case, when acomparison is made, the comparison may be made after a certain treatmentperiod, e.g., 0.5, 1, 2, 3 or 4 months. Preferably the treatment periodis 3 or more months.

A further advantage of the present invention is that one or more SGLT2inhibitors may effectively be administered to an equine animal orally,e.g., in liquid form. Moreover, SGLT2 inhibitors according to thepresent invention can be administered only once per day. Theseadvantages allow for optimal dosing and compliance of the treated equineanimal.

Generally, the use of SGLT2 inhibitors according to the presentinvention may thus attenuate, delay or prevent the progression of ametabolic disorder, e.g., the metabolic disorders disclosed herein, ormay delay or prevent the onset of metabolic disorders and theircomplications in equine animals.

The invention also provides methods of treating or preventing metabolicdisorders in equine animals, comprising administering to an equineanimal in need of such treatment or prevention an effective dose of oneor more SGLT2 inhibitors as described herein.

In a preferred embodiment, the present invention thus provides the useof one or more SGLT2 inhibitors or pharmaceutically acceptable formsthereof in the treatment and/or prevention of recurrent laminitisassociated with hyperinsulinemia in equine animals, preferably horses,with insulin resistance.

In another preferred embodiment, the present invention thus provides theuse of one or more SGLT2 inhibitors or pharmaceutically acceptable formsthereof in the treatment and/or prevention of recurrent laminitisassociated with Equine Metabolic Syndrome (EMS) in equine animals,preferably horses.

In yet another preferred embodiment, the present invention thus providesthe use of one or more SGLT2 inhibitors or pharmaceutically acceptableforms thereof in the treatment and/or prevention of the clinicalconditions/signs associated with Equine Metabolic Syndrome (EMS) orEquine Metabolic Syndrome (EMS) in equine animals, preferably horses,wherein preferably said clinical conditions/signs may be one or moredisorder selected from insulin resistance, hyperinsulinemia, impairedglucose tolerance, dyslipidemia, dysadipokinemia, subclinicalinflammation, systemic inflammation, low grade systemic inflammation,which also comprises adipose tissue, obesity, regional adiposity,laminitis, vascular dysfunction, hypertension, hepatic lipidosis,atherosclerosis, hyperadrenocorticism, Pituitary Pars IntermediaDysfunction and/or Equine Metabolic Syndrome.

Definitions

All values and concentrations presented herein are subject to inherentvariations acceptable in biological science within an error of ±10%. Theterm “about” also refers to this acceptable variation.

Treatment effects disclosed herein (such as an improvement, reduction ordelayed onset of a disorder, disease or condition, or the improvement,reduction, increase or delay of any effect, index, marker level or otherparameter relating to a disorder, disease or condition) may be observedwith a statistical significance of p<0.05, preferably <0.01.

When reference is made herein to a deviation (e.g., an increase,elevation, excess, prolongation, raise, reduction, decrease,improvement, delay, abnormal levels, or any other change, alteration ordeviation with respect to a reference), the deviation may be, e.g., by5% or more, particularly 10% or more, more particularly 15% or more,more particularly 20% or more, more particularly 30% or more, moreparticularly 40% or more, or more particularly 50% or more, with respectto the relevant reference value, unless otherwise stated. Typically, thedeviation will be by at least 10%, i.e., 10% or more. The deviation mayalso be by 20%. The deviation may also be by 30%. The deviation may alsobe by 40%. The relevant reference value may be generated from a group ofreference animals which are treated with placebo instead of an SGLT2inhibitor.

Herein, an excursion, e.g., an insulin excursions or glucose excursion,designates a change in concentration or level in blood over time. Themagnitude of excursions, e.g., insulin excursions or glucose excursionsmay be expressed as area-under-curve (AUC) values.

Herein, the terms “active substance” or “active ingredient” encompassone or more SGLT2 inhibitors or any pharmaceutically acceptable formthereof (e.g., a prodrug or a crystalline form), for use according tothe invention. In the case of a combination with one or additionalactive compound, the terms “active ingredient” or “active substance” mayalso include the additional active compound.

Herein, the expression “associated with”, in particular encompasses theexpression “caused by”.

Herein, ivGTT refers to an intravenous glucose tolerance test. In anivGTT, 0.2 g dextrose per kg body mass may typically be employed.

Herein, ivITT refers to an intravenous insulin tolerance test. In anivITT, 0.03 U insulin per kg body mass may typically be employed.

Herein, CGIT refers to a combined glucose-insulin tolerance test. In aCGIT, 0.15 mg glucose per kg body mass and 0.1 U insulin per kg bodymass may typically be employed.

Herein, OST refers to an oral sugar test. In an OST, 0.15 mL corn syrupper kg body mass may typically be employed.

SGLT2 Inhibitors

SGLT2 inhibitors for use according to the invention include, but are notlimited to, glucopyranosyl-substituted benzene derivatives, for exampleas described in WO01/27128 (ref. 7), WO03/099836 (ref. 8), WO2005/092877(ref. 9), WO2006/034489 (ref. 10), WO2006/064033 (ref 11), WO2006/117359(ref 12), WO2006/117360 (ref 13), WO2007/025943 (ref 14), WO2007/028814(ref. 15), WO2007/031548 (ref. 16), WO2007/093610 (ref. 17),WO2007/128749 (ref. 18), WO2008/049923 (ref. 19), WO2008/055870 (ref.20), WO2008/055940 (ref. 21), WO2009/022020 (ref. 22) or WO2009/022008(ref 23), all hereby incorporated by reference.

Moreover, a SGLT2 inhibitor for use according to the invention may beselected from the group consisting of the following compounds orpharmaceutically acceptable forms thereof:

-   -   (1) a glucopyranosyl-substituted benzene derivative of the        formula (1)

-   -   -   wherein R¹ denotes cyano, Cl or methyl (most preferably            cyano);        -   R² denotes H, methyl, methoxy or hydroxy (most preferably H)            and        -   R³ denotes cyclopropyl, hydrogen, fluorine, chlorine,            bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl,            sec-butyl, iso-butyl, tert-butyl, 3-methyl-but-1-yl,            cyclobutyl, cyclopentyl, cyclohexyl, 1-hydroxy-cyclopropyl,            1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,            1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl,            trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,            hydroxymethyl, 3-hydroxy-propyl,            2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,            1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,            2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl,            2-methoxy-ethyl, 2-ethoxy-ethyl, hydroxy, difluoromethyloxy,            trifluoromethyloxy, 2-methyloxy-ethyloxy, methyl sulfanyl,            methyl sulfinyl, methlysulfonyl, ethyl sulfinyl, ethyl            sulfonyl, trimethylsilyl, (R)-tetrahydrofuran-3-yloxy or            (S)-tetrahydrofuran-3-yloxy or cyano;        -   wherein R3 is preferably selected from cyclopropyl, ethyl,            ethinyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or            (S)-tetrahydrofuran-3-yloxy; and most preferably R3 is            cyclopropyl,        -   or a derivative thereof wherein one or more hydroxyl groups            of the β-D-glucopyranosyl group are acylated with groups            selected from (C₁₋₁₈-alkyl)carbonyl,            (C₁₋₁₈-alkyl)oxycarbonyl, phenyl carbonyl and            phenyl-(C₁₋₃-alkyl)-carbonyl;

    -   (2)        1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene,        represented by formula (2):

-   -   (3) Dapagliflozin, represented by formula (3):

-   -   (4) Canagliflozin, represented by formula (4):

-   -   (5) Empagliflozin, represented by formula (5):

-   -   (6) Luseogliflozin, represented by formula (6):

-   -   (7) Tofogliflozin, represented by formula (7):

-   -   (8) Ipragliflozin, represented by formula (8):

-   -   (9) Ertugliflozin, represented by formula (9):

-   -   (10) Atigliflozin, represented by formula (10):

-   -   (11) Remogliflozin, represented by formula (11):

-   -   (12) a thiophene derivative of the formula (12)

-   -   -   wherein R denotes methoxy or trifluoromethoxy;

    -   (13)        1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene        as described in WO2005/012326, represented by formula (13);

-   -   (14) a spiroketal derivative of the formula (14):

-   -   -   wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl,            isopropyl or tert. butyl;

    -   (15) a pyrazole-O-glucoside derivative of the formula (15)

-   -   -   wherein        -   R¹ denotes C₁₋₃-alkoxy,        -   L¹, L² independently of each other denote H or F,        -   R⁶ denotes H, (C₁₋₃-alkyl)carbonyl, (C₁₋₆-alkyl)oxycarbonyl,            phenyloxycarbonyl, benzyloxycarbonyl or benzylcarbonyl;

    -   (16) a compound of the formula (16):

-   -   (17) and Sergliflozin, represented by formula (17):

The term “dapagliflozin” as employed herein refers to dapagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described inWO03/099836 (ref. 8) for example. Preferred hydrates, solvates andcrystalline forms are described in the patent applications WO2008/116179(ref. 24) and WO2008/002824 (ref 25) for example.

The term “canagliflozin” as employed herein refers to canagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described inWO2005/012326 (ref. 26) and WO2009/035969 (ref. 27) for example.Preferred hydrates, solvates and crystalline forms are described in thepatent application WO2008/069327 (ref. 28) for example.

The term “empagliflozin” as employed herein refers to empagliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described inWO2005/092877 (ref. 9), WO2006/120208 (ref. 29) and WO2011/039108 (ref.30) for example. A preferred crystalline form is described in the patentapplications WO2006/117359 (ref. 12) and WO2011/039107 (ref 31) forexample.

The term “atigliflozin” as employed herein refers to atigliflozin of theabove structure as well as pharmaceutically acceptable forms thereof,including hydrates and solvates thereof, and crystalline forms thereof.The compound and methods of its synthesis are described in WO2004/007517(ref. 32) for example.

The term “ipragliflozin” as employed herein refers to ipragliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described inWO2004/080990 (ref. 33), WO2005/012326 (ref. 26) and WO2007/114475 (ref.34) for example.

The term “tofogliflozin” as employed herein refers to tofogliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound and methods of its synthesis are described inWO2007/140191 (ref 35) and WO2008/013280 (ref 36) for example.

The term “luseogliflozin” as employed herein refers to luseogliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof.

The term “ertugliflozin” as employed herein refers to ertugliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including hydrates and solvates thereof, and crystalline formsthereof. The compound is described for example in WO2010/023594 (ref.37).

The term “remogliflozin” as employed herein refers to remogliflozin ofthe above structure as well as pharmaceutically acceptable formsthereof, including prodrugs of remogliflozin, in particularremogliflozin etabonate, including hydrates and solvates thereof, andcrystalline forms thereof. Methods of its synthesis are described in thepatent applications EP1213296 (ref. 38) and EP1354888 (ref. 39) forexample.

The term “sergliflozin” as employed herein refers to sergliflozin of theabove structure as well as pharmaceutically acceptable forms thereof,including prodrugs of sergliflozin, in particular sergliflozinetabonate, including hydrates and solvates thereof, and crystallineforms thereof. Methods for its manufacture are described in the patentapplications EP1344780 (ref. 40) and EP1489089 (ref. 41) for example.

The compound of formula (16) above and its manufacture are described forexample in WO2008/042688 (ref 42) or WO2009/014970 (ref 43).

Preferred SGLT2 inhibitors are glucopyranosyl-substituted benzenederivatives. Optionally, one or more hydroxyl groups of theglucopyranosyl group in such one or more SGLT2 inhibitors may beacylated with groups selected from (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, phenyl carbonyl andphenyl-(C₁₋₃-alkyl)-carbonyl.

More preferred are glucopyranosyl-substituted benzonitrile derivativesof formula (1) as disclosed herein above. Yet more preferred areglucopyranosyl-substituted benzonitrile derivatives of formula (18):

wherein R3 denotes cyclopropyl, hydrogen, fluorine, chlorine, bromine,iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl,tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl, cyclohexyl,1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl, 1-hydroxy-cyclopentyl,1-hydroxy-cyclohexyl, ethinyl, ethoxy, difluoromethyl, trifluoromethyl,pentafluoroethyl, 2-hydroxyl-ethyl, hydroxymethyl, 3-hydroxy-propyl,2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl,1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,2-methyloxy-ethyloxy, methyl sulfanyl, methylsulfinyl, methlysulfonyl,ethyl sulfinyl, ethylsulfonyl, trimethylsilyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano(wherein R3 is preferably selected from cyclopropyl, ethyl, ethinyl,ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; andR3 most preferably is cyclopropyl, or a derivative thereof wherein oneor more hydroxyl groups of the β-D-glucopyranosyl group are acylatedwith groups selected from (C₁₋₁₈-alkyl)carbonyl,(C₁₋₁₈-alkyl)oxycarbonyl, phenyl carbonyl andphenyl-(C₁₋₃-alkyl)-carbonyl.

Preferably, such SGLT2 inhibitor is1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene asshown in formula (2) (also referred to herein as “compound A”).Optionally, one or more hydroxyl groups of the β-D-glucopyranosyl groupof compound A may be acylated with groups selected from(C₁₋₁₈-alkyl)carbonyl, (C₁₋₁₈-alkyl)oxycarbonyl, phenyl carbonyl andphenyl-(C₁₋₃-alkyl)-carbonyl.

Thus, in preferred embodiments, a SGLT2 inhibitor according to thepresent invention is a glucopyranosyl-substituted benzene derivativeSGLT2 inhibitor, preferably a SGLT2 inhibitor of formula (1), morepreferably of formula (18), or yet more preferably of formula (2) (i.e.,compound A), in each case as defined herein above.

Metabolic Disorders

According to the invention, metabolic disorders or metabolic diseasesare all kinds of disturbances of the energy metabolism, affecting e.g.,the turnover of carbohydrates and/or of fat. It is preferred to affectthe control of the energy metabolism, especially the glucose metabolismby influencing the responsible regulatory network, e.g., via modulationof the activity and/or concentrations of insulin.

The metabolic disorder may be an insulin-related disorder. Inparticular, the metabolic disorder may be insulin resistance (or,equivalently, impaired insulin sensitivity). Insulin resistance may beassociated with a further metabolic disorder or clinical condition/sign,e.g., insulin resistance may be associated with impaired glucosetolerance, dyslipidemia, dysadipokinemia, subclinical inflammation,systemic inflammation, low grade systemic inflammation, which alsocomprises adipose tissue, obesity and/or regional adiposity.

Additionally or alternatively, insulin resistance may be associated withlaminitis. Additionally or alternatively, insulin resistance may beassociated with vascular dysfunction. Additionally or alternatively,insulin resistance may be associated with hypertension. Additionally oralternatively, insulin resistance may be associated withhyperadrenocorticism. Additionally or alternatively, insulin resistancemay be associated with hepatic lipidosis. Laminitis, vasculardysfunction, hypertension, hyperadrenocorticism and/or hepatic lipidosesare clinical condition/signs associated with EMS and/or PPID. Thus,additionally or alternatively, insulin resistance may be associated withEMS and/or PPID.

The metabolic disorder may be hyperinsulinemia. Hyperinsulinemia may beassociated with a further metabolic disorder or clinical condition/sign,e.g. hyperinsulinemia may be associated with obesity and/or regionaladiposity. Additionally or alternatively, hyperinsulinemia may beassociated with laminitis. Additionally or alternatively,hyperinsulinemia may be associated with vascular dysfunction.Additionally or alternatively, hyperinsulinemia may be associated withhypertension. Additionally or alternatively, hyperinsulinemia may beassociated with hepatic lipidosis. Laminitis, vascular dysfunction,hypertension and/or hepatic lipidoses are clinical condition/signsassociated with EMS and/or PPID. Thus or alternatively, hyperinsulinemiamay be associated with EMS and/or PPID.

In preferred embodiments, the metabolic disorder may be insulinresistance, hyperinsulinemia and/or a clinical condition/sign associatedwith insulin resistance and/or hyperinsulinemia. Treatment or preventionof a metabolic disorder of an equine animal in accordance with theinvention may be treatment or prevention of insulin resistance and/orhyperinsulinemia.

Clinical conditions/signs associated with insulin resistance and/orhyperinsulinemia are e.g., impaired glucose tolerance, dyslipidemia,dysadipokinemia, subclinical inflammation, systemic inflammation, lowgrade systemic inflammation, which also comprises adipose tissue,obesity and/or regional adiposity. Treatment and/or prevention of ametabolic disorder of an equine animal in accordance with the inventionmay be the treatment and/or prevention of impaired glucose tolerance,dyslipidemia, dysadipokinemia, subclinical inflammation, systemicinflammation, low grade systemic inflammation, which also comprisesadipose tissue, obesity and/or regional adiposity in an equine animal.That equine animal may also suffer from laminitis, vascular dysfunction,hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism,PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia may be impaired glucose tolerance.Hence, the treatment or prevention of a metabolic disorder of an equineanimal in accordance with the invention may be the treatment orprevention of impaired glucose tolerance, preferably associated withinsulin resistance and/or hyperinsulinemia in an equine animal. Thatequine animal may also suffer from laminitis, vascular dysfunction,hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism,PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia may be dyslipidemia. Hence, thetreatment and/or prevention of a metabolic disorder of an equine animalin accordance with the invention may be the treatment and/or preventionof dyslipidemia, preferably associated with insulin resistance and/orhyperinsulinemia in an equine animal. That equine animal may also sufferfrom laminitis, vascular dysfunction, hypertension, hepatic lipidosis,atherosclerosis, hyperadrenocorticism, PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia may be dysadipokinemia. Hence, thetreatment and/or prevention of a metabolic disorder of an equine animalin accordance with the invention may be treatment and/or prevention ofdysadipokinemia, preferably associated with insulin resistance and/orhyperinsulinemia in an equine animal. That equine animal may also sufferfrom laminitis, vascular dysfunction, hypertension, hepatic lipidosis,atherosclerosis, hyperadrenocorticism, PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia may be subclinical inflammation orsystemic inflammation, in particular low grade systemic inflammation,which also comprises adipose tissue. Hence, the treatment and/orprevention of a metabolic disorder of an equine animal in accordancewith the invention may be treatment and/or prevention of subclinicalinflammation or systemic inflammation, in particular low grade systemicinflammation, which also comprises adipose tissue, preferably associatedwith insulin resistance and/or hyperinsulinemia in an equine animal.That equine animal may also suffer from laminitis, vascular dysfunction,hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism,PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia may be obesity. Hence, the treatmentand/or prevention of a metabolic disorder of an equine animal inaccordance with the invention may be treatment and/or prevention ofobesity, preferably associated with insulin resistance and/orhyperinsulinemia in an equine animal. That equine animal may also sufferfrom laminitis, vascular dysfunction, hypertension, hepatic lipidosis,atherosclerosis, hyperadrenocorticism, PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia may be regional adiposity. Hence, thetreatment and/or prevention of a metabolic disorder of an equine animalin accordance with the invention may be treatment and/or prevention ofregional adiposity, preferably associated with insulin resistance and/orhyperinsulinemia in an equine animal. That equine animal may also sufferfrom laminitis, vascular dysfunction, hypertension, hepatic lipidosis,atherosclerosis, hyperadrenocorticism, PPID and/or EMS.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be laminitis. In someembodiments, laminitis may be associated with obesity and/or regionaladiposity. In some embodiments, when a metabolic disorder or clinicalcondition/sign is laminitis, the equine animal is suffering from EMSand/or PPID. The present invention preferably prevents the developmentand/or recurrence of laminitis, e.g., in an equine animal suffering fromEMS and/or PPID.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be vascular dysfunction, e.g.,vascular dysfunction in an equine animal's hoof. In some embodiments,vascular dysfunction may be associated with obesity and/or regionaladiposity. In some embodiments, when a metabolic disorder or clinicalcondition/sign is vascular dysfunction, the equine animal is sufferingfrom EMS and/or PPID. The present invention preferably prevents thedevelopment and/or recurrence of vascular dysfunction, e.g., in anequine animal suffering from EMS and/or PPID.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be hypertension. In someembodiments, hypertension may be associated with regional obesity and/orregional adiposity. In some embodiments, when a metabolic disorder orclinical condition/sign is hypertension, the equine animal is sufferingfrom EMS and/or PPID. The present invention preferably prevents thedevelopment and/or recurrence of hypertension, e.g., in an equine animalsuffering from EMS and/or PPID.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be hepatic lipidosis. In someembodiments, hepatic lipidosis may be associated with regional obesityand/or regional adiposity. In some embodiments, when a metabolicdisorder or clinical condition/sign is hepatic lipidosis, the equineanimal is suffering from EMS and/or PPID. The present inventionpreferably prevents the development and/or recurrence of hepaticlipidosis, e.g., in an equine animal suffering from EMS and/or PPID.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be atherosclerosis, In someembodiments, atherosclerosis may be associated with systemicinflammation, subclinical inflammation, low grade systemic inflammation,which also comprises adipose tissue. In some embodiments, when ametabolic disorder or clinical condition/sign is atherosclerosis, theequine animal is suffering from EMS and/or PPID. The present inventionpreferably prevents the development and/or recurrence ofatherosclerosis, e.g., in an equine animal suffering from EMS and/orPPID.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be hyperadrenocorticism. In someembodiments, hyperadrenocorticism may be associated with systemicinflammation, subclinical inflammation, low grade systemic inflammation,which also comprises adipose tissue. In some embodiments, when ametabolic disorder or clinical condition/sign is hyperadrenocorticism,the equine animal is suffering from EMS and/or PPID. The presentinvention preferably provides for the treatment and/or prevention ofhyperadrenocorticism, i.e., it prevents the development and/orrecurrence of hyperadrenocorticism, e.g., in an equine animal sufferingfrom EMS and/or PPID.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be Equine Metabolic Syndrome(EMS). In some embodiments, EMS may be associated with obesity and/orregional adiposity.

Herein, a metabolic disorder or clinical condition/sign, e.g., ametabolic disorder or clinical condition/sign associated with insulinresistance and/or hyperinsulinemia, may be Equine Pituitary ParsIntermedia Dysfunction (PPID). In some embodiments, PPID may beassociated with hyperadrenocorticism.

In some embodiments, the equine animal treated in accordance with theinvention (e.g., for hyperinsulinemia, insulin resistance, and/or aclinical condition/sign associated with insulin resistance and/orhyperinsulinemia) is suffering from laminitis, vascular dysfunction,PPID and/or EMS.

In some embodiments, impaired glucose tolerance may be associated withobesity and/or regional adiposity. Hence, the treatment and/orprevention of a metabolic disorder of an equine animal in accordancewith the invention may be treatment and/or prevention of impairedglucose tolerance associated with obesity and/or regional adiposity inan equine animal.

In some embodiments, impaired glucose tolerance may be associated withhyperadrenocorticism. Hence, the treatment and/or prevention of ametabolic disorder of an equine animal in accordance with the inventionmay be treatment and/or prevention of impaired glucose toleranceassociated with hyperadrenocorticism in an equine animal.

Insulin resistance can be described as the condition in which normalamounts of insulin are inadequate to produce a normal insulin responsefrom fat, muscle and liver cells. Insulin resistance in fat cellsreduces the effects of insulin and results in elevated hydrolysis ofstored triglycerides in the absence of measures which either increaseinsulin sensitivity or which provide additional insulin. Increasedmobilization of stored lipids in these cells elevates free fatty acidsin the blood plasma. Insulin resistance in muscle cells reduces glucoseuptake (and so local storage of glucose as glycogen), whereas insulinresistance in liver cells results in impaired glycogen synthesis and afailure to suppress glucose production. Elevated blood fatty acidlevels, reduced muscle glucose uptake, and increased liver glucoseproduction, may all contribute to elevated blood glucose levels(hyperglycemia), although hyperglycemia is not a major issue e.g., ininsulin-resistant horses. In the horse, when insulin-resistant targettissues, e.g., skeletal muscle, have a reduced capacity for glucoseuptake, the pancreas is stimulated to release more insulin, leading tohyperinsulinemia.

Surrogate indices of insulin sensitivity may be calculated according tothe QUICKI (quantitative insulin sensitivity check index:1/log(glucose*insulin)) for basal blood level. For dynamic testings,e.g. during a glucose challenge a modified Belfiore Index(1/log(ΔAUC-glucose*ΔAUC-insulin)) can be employed.

Insulin resistance may be present in association with regionaladiposity, e.g., cresty neck, tail fat depots, visceral adiposity,hypertension and dyslipidemia involving elevated triglycerides, smalldense low-density lipoprotein (sdLDL) particles, and decreased HDLcholesterol levels. With respect to visceral adiposity, a great deal ofevidence in humans suggests two strong links with insulin resistance.First, unlike subcutaneous adipose tissue, visceral adipose cellsproduce significant amounts of proinflammatory cytokines such as tumornecrosis factor-alpha (TNF-a), and Interleukins-1 and -6, etc. Innumerous experimental models, these proinflammatory cytokines profoundlydisrupt normal insulin action in fat and muscle cells, and may be amajor factor in causing the whole-body insulin resistance observed inhuman patients with visceral adiposity. Similar, in equines thedifferent excessive regional fat depots contribute to low grade systemicinflammation. Second, adiposity is related to an accumulation of fat inthe liver, a condition known as nonalcoholic fatty liver disease (NAFLD)in humans and hepatic lipidosis in general terms, e.g., in equines. Theresult of NAFLD is an excessive release of free fatty acids into thebloodstream (due to increased lipolysis), and an increase in hepaticglucose production, both of which have the effect of exacerbatingperipheral insulin resistance. The cause of the vast majority of casesof insulin resistance remains unknown. There is clearly an inheritedcomponent. However, there are some grounds for suspecting that insulinresistance is related to a high-carbohydrate diet. Inflammation alsoseems to be implicated in causing insulin resistance.

Hyperinsulinemia may be described as a condition in which there areexcess levels, i.e., more than about 10-20 μIU/mL of insulin circulatingin the blood. As mentioned, it is commonly present in cases of, and maybe a consequence of, insulin resistance in equine animals.

Impaired glucose tolerance can be described as condition in which theresponse to a after a glycemic challenge e.g., after a meal or after aloading test (glucose tolerance test) the glycemic peak of the glucoseexcursion is higher and/or the duration of the glucose excursion isprolonged.

Dyslipidemia or hyperlipidemia is the presence of raised or abnormallevels of lipids and/or lipoproteins in the blood. Lipid and lipoproteinabnormalities are regarded as a highly modifiable risk factor forcardiovascular disease due to the influence of cholesterol, one of themost clinically relevant lipid substances, on atherosclerosis. Glycerolis a precursor for the synthesis of triacylglycerols (triglycerides) andof phospholipids in the liver and adipose tissue. When the body usesstored fat as a source of energy, glycerol and fatty acids are releasedinto the bloodstream after hydrolysis of the triglycerides. The glycerolcomponent can be converted to glucose by the liver and provides energyfor cellular metabolism. Normal levels of free fatty acids in the bloodequine animals are concentrations of 50 to 100 mg/dl (0.6 to 1.2mmol/l). Normal levels of triglycerides are e.g., up to around 50 mg/dL.Normal levels of blood cholesterol are, e.g., around 120 mg/dl for thehorse.

Dysadipokinemia can be described as a condition in which the circulatingplasma levels of biologically active substances produced in adiposetissue that act in an autocrine/paracrine or endocrine fashion isdeviated. e.g., an elevation of leptin and/or a reduction ofadiponectin.

Subclinical inflammation or systemic inflammation, in particular lowgrade systemic inflammation is characterized by increased expression andsecretion of pro-inflammatory cytokines such as tumor necrosisfactor-alpha and/or lower expression and secretion of anti-inflammatorycytokines e.g., interleukin-10 and/or their respective receptors.

Laminitis can be described as an inflammation or edema of the sensitivelaminae of the hoof resulting e.g., in lameness. The laminae bond thehoof wall to the pedal bone, which supports the entire weight of thehorse or equine. Severe cases of laminitis can result in the pedal bonerotation that may progress to perforation of the sole. Laminitis inducedlameness can be graded e.g., by visual score of behavior in standingposition and moving performance.

Vascular dysfunction can be described as impaired action ofendothelium-dependent insulin induced vasodilation, as well alterationof direct insulin effects on vascular smooth muscles, e.g., relaxationand reactivity to vasoconstrictor stimuli.

Equine Metabolic Syndrome is defined by the presence of insulinresistance, obesity and/or regional adiposity. The EMS phenotype mayalso comprise dyslipidemia, dyadipokinemia and/or hypertension. Thesyndrome can be described as a combination of medical disorders thatincrease the risk of developing associated pathologies, e.g., laminitis.The equine metabolic syndrome might also be associated with otherdisorders like hepatic lipidosis or infertility.

Obesity can be described as a medical condition in which excess body fathas accumulated to the extent that it may have an adverse effect onhealth, leading to reduced life expectancy. In equines e.g., duringphysical examination body condition scores of equal or more than 7 (outof 9) are encountered.

Regional adiposity in equine animals can be described as a medicalcondition in which body fat (adipose tissue) accumulates in specificregions, e.g., the neck (cresty neck), either side of the tailhead,prepuce, in fat pads in the rump area, the mammary gland region, and/orin supraorbital fat pads. Regional adiposity also encompasses visceraladiposity, e.g., increased omental fat.

Obesity and or regional adiposity is associated with many otherdiseases, particularly heart disease, type 2 diabetes (though this israre in horses), certain types of cancer, osteoarthritis and/orstrangulating lipoma. Obesity is most commonly caused by a combinationof excessive dietary calories, lack of physical activity, and geneticsusceptibility, though a limited number of cases are due to a singlecause, e.g., solely to genetics.

Atherosclerosis can be described as a condition in which an artery wallthickens as the result of a build-up of fatty materials such ascholesterol. It is a syndrome affecting arterial blood vessels, achronic inflammatory response in the walls of arteries, in large partdue to the accumulation of macrophage white blood cells and promoted bylow density (especially small particle) lipoproteins (plasma proteinsthat carry cholesterol and triglycerides) without adequate removal offats and cholesterol from the macrophages by functional high densitylipoproteins (HDL). It is commonly referred to as a hardening or furringof the arteries. It is caused by the formation of multiple plaqueswithin the arteries.

Pituitary Pars Intermedia Dysfunction (PPID) is a common disease ofolder horses and ponies. Hypothalamic dopaminergic neurodegenerationresults in an elevated adrenocorticotropic hormone (ACTH) production inthe Pituitary Pars Intermedia and leads to hyperadrenocorticism.Clinical signs include hirsutism (a long, often curly coat that may notshed), polydipsia/polyuria, excessive sweating, weight loss, musclewasting, regional fat deposits, lethargy, infections e.g., sinusitisand/or laminitis.

Equine animals. Herein, the term “equine animal” may be usedinterchangeably with the term “equine” and encompasses any member of thegenus Equus. It encompasses, e.g., any horse or pony, the taxonomicdesignations Equus ferus and/or Equus caballus, and/or the subspeciesEquus ferus caballus. The equine animal may, e.g., be a domestic horse.

Pharmaceutically acceptable forms. Herein, references to SGLT2inhibitors and/or their use according to the invention encompasspharmaceutically acceptable forms of the SGLT2 inhibitors, unlessotherwise stated.

According to the invention, any pharmaceutically acceptable form of theSGLT2 inhibitor, e.g., of formula (1), preferably formula (18), morepreferably formula (2), may be used. E.g., a crystalline form may beused. Prodrug forms are also encompassed by the present invention.

Prodrug forms may include, e.g., esters and/or hydrates. The termprodrug is also meant to include any covalently bonded carrier whichreleases the active compound of the invention in vivo when the prodrugis administered to a mammalian subject. Prodrugs of a compound of theinvention may be prepared by modifying functional groups present in thecompound of the invention in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompound of the invention.

Crystalline forms for use according to the invention include a complexof one or more SGLT2 inhibitors with one or more amino acids (see e.g.,WO 2014/016381). An amino acid for such use may be a natural amino acid.The amino acid may be a proteogenic amino acid (includingL-hydroxyproline), or a non-proteogenic amino acid. The amino acid maybe a D- or an L-amino acid. In some preferred embodiments the amino acidis proline (L-proline and/or D-proline, preferably L-proline). E.g., acrystalline complex of1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene(formula (2); compound A) with proline (e.g. L-proline) is preferred.

Thus, herein is disclosed a crystalline complex between one or morenatural amino acids and an SGLT2 inhibitor, e.g., a crystalline complexbetween one or more natural amino acids and a glucopyranosyl-substitutedbenzene derivative SGLT2 inhibitor, preferably a SGLT2 inhibitor offormula (1), more preferably of formula (18) or yet more preferably offormula (2) (compound A). Thus, herein is disclosed a crystallinecomplex between one or more natural amino acids and1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene(compound A).

Further disclosed herein is the use of one or more crystalline complexesas defined hereinbefore or hereinafter for preparing a pharmaceuticalcomposition which is suitable for the treatment or prevention ofdiseases or conditions which can be influenced by inhibitingsodium-dependent glucose co-transporter SGLT, preferably SGLT2. Furtherdisclosed herein is the use of one or more crystalline complexes asdefined hereinbefore or hereinafter for preparing a pharmaceuticalcomposition for inhibiting the sodium-dependent glucose co-transporterSGLT2.

A crystalline complex between one or more natural amino acids (e.g.proline, preferably L-proline) and an SGLT2 inhibitor, is a preferredpharmaceutically acceptable form of a SGLT2 inhibitor for use accordingto the present invention. In particular, a crystalline complex betweenone or more natural amino acids (e.g. proline, preferably L-proline) anda glucopyranosyl-substituted benzene derivative SGLT2 inhibitor,preferably a SGLT2 inhibitor of formula (1), more preferably of formula(18) or yet more preferably of formula (2) (compound A) is a preferredpharmaceutically acceptable form of a SGLT2 inhibitor for use accordingto the present invention. A crystalline complex between one or morenatural amino acids (e.g., proline, preferably L-proline) and1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene(compound A) is particularly preferred as a pharmaceutically acceptableform of a SGLT2 inhibitor for use according to the present invention.

Also disclosed herein is a method for making one or more crystallinecomplexes as defined hereinbefore and hereinafter, said methodcomprising the following steps:

-   -   a. preparing a solution of the one or more SGLT2 inhibitors        (e.g., a glucopyranosyl-substituted benzene derivative, or a        SGLT2 inhibitor of formula (1), preferably formula (18) or more        preferably formula (2), i.e., compound A) and the one or more        natural amino acids in a solvent or a mixture of solvents;    -   b. storing the solution to precipitate the crystalline complex        out of solution;    -   c. removing the precipitate from the solution; and    -   d. drying the precipitate optionally until any excess of said        solvent or mixture of solvents has been removed.

A certain pharmaceutical activity is of course the basic prerequisite tobe fulfilled by a pharmaceutically active agent before same is approvedas a medicament on the market. However, there are a variety ofadditional requirements a pharmaceutically active agent has to complywith. These requirements are based on various parameters which areconnected with the nature of the active substance itself. Without beingrestrictive, examples of these parameters are the stability of theactive agent under various environmental conditions, its stabilityduring production of the pharmaceutical formulation and the stability ofthe active agent in the final medicament compositions. Thepharmaceutically active substance used for preparing the pharmaceuticalcompositions should be as pure as possible and its stability inlong-term storage must be guaranteed under various environmentalconditions. This is essential to prevent the use of pharmaceuticalcompositions which contain, in addition to the actual active substance,breakdown products thereof, for example. In such cases the content ofactive substance in the medicament might be less than that specified.

Uniform distribution of the medicament in the formulation is a criticalfactor, particularly when the medicament has to be given in low doses.To ensure uniform distribution, the particle size of the activesubstance can be reduced to a suitable level, e.g., by grinding. Sincebreakdown of the pharmaceutically active substance as a side effect ofthe grinding (or micronizing) has to be avoided as far as possible, inspite of the hard conditions required during the process, it isessential that the active substance should be highly stable throughoutthe grinding process. Only if the active substance is sufficientlystable during the grinding process it is possible to produce ahomogeneous pharmaceutical formulation which always contains thespecified amount of active substance in a reproducible manner.

Another problem which may arise in the grinding process for preparingthe desired pharmaceutical formulation is the input of energy caused bythis process and the stress on the surface of the crystals. This may incertain circumstances lead to polymorphous changes, to amorphization orto a change in the crystal lattice. Since the pharmaceutical quality ofa pharmaceutical formulation requires that the active substance shouldalways have the same crystalline morphology, the stability andproperties of the crystalline active substance are subject to stringentrequirements from this point of view as well.

The stability of a pharmaceutically active substance is also importantin pharmaceutical compositions for determining the shelf life of theparticular medicament; the shelf life is the length of time during whichthe medicament can be administered without any risk. High stability of amedicament in the abovementioned pharmaceutical compositions undervarious storage conditions is therefore an additional advantage for boththe patient and the manufacturer.

The absorption of moisture reduces the content of pharmaceuticallyactive substance as a result of the increased weight caused by theuptake of water. Pharmaceutical compositions with a tendency to absorbmoisture have to be protected from moisture during storage, e.g., by theaddition of suitable drying agents or by storing the drug in anenvironment where it is protected from moisture. Preferably, therefore,a pharmaceutically active substance should be at best slightlyhygroscopic.

Furthermore, the availability of a well-defined crystalline form allowsthe purification of the drug substance by recrystallization.

Apart from the requirements indicated above, it should be generallyborne in mind that any change to the solid state of a pharmaceuticalcomposition which is capable of improving its physical and chemicalstability gives a significant advantage over less stable forms of thesame medicament.

A crystalline complex between a natural amino acid and one or more SGLT2inhibitors (e.g. a glucopyranosyl-substituted benzene derivative or aSGLT2 inhibitor of formula (1), or formula (18) or, particularly, offormula (2), i.e. compound A) fulfills important requirements mentionedhereinbefore.

Preferably the natural amino acid is present in either its (D) or (L)enantiomeric form, most preferably as the (L) enantiomer.

Furthermore those crystalline complexes according to this invention arepreferred which are formed between the one or more SGLT2 inhibitors(e.g. of formula (1), preferably formula (18) or, particularly, offormula (2), i.e. compound A) and one natural amino acid, mostpreferably between the compound A and the (L) enantiomer of a naturalamino acid.

Preferred amino acids according to this invention are selected from thegroup consisting of phenylalanine and proline, in particular (L)-prolineand (L)-phenylalanine.

According to a preferred embodiment the crystalline complex ischaracterized in that the natural amino acid is proline, in particular(L)-proline.

Preferably the molar ratio of the one or more SGLT2 inhibitors (e.g. offormula (1), preferably formula (18) or, particularly, of formula (2),i.e. compound A) and the natural amino acid is in the range from about2:1 to about 1:3; more preferably from about 1.5:1 to about 1:1.5, evenmore preferably from about 1.2:1 to about 1:1.2, most preferably about1:1. In the following such an embodiment is referred to as “complex(1:1)” or “1:1 complex”.

Therefore a preferred crystalline complex according to this invention isa complex (1:1) between said SGLT2 inhibitor (e.g. of formula (1),preferably formula (18) or, particularly, of formula (2), i.e. compoundA) and proline; in particular of said SGLT2 inhibitor and L-proline.

According to a preferred embodiment the crystalline complex, in theparticular the 1:1 complex of said SGLT2 inhibitor with L-proline, is ahydrate.

Preferably the molar ratio of the crystalline complex and water is inthe range from about 1:0 to 1:3; more preferably from about 1:0 to 1:2,even more preferably from about 1:0.5 to 1:1.5, most preferably about1:0.8 to 1:1.2, in particular about 1:1.

The crystalline complex of said SGLT2 inhibitor with proline, inparticular with L-proline and water, may be identified and distinguishedfrom other crystalline forms by means of their characteristic X-raypowder diffraction (XRPD) patterns.

For example, a crystalline complex of compound A with L-proline ispreferably characterized by an X-ray powder diffraction pattern thatcomprises peaks at 20.28, 21.14 and 21.64 degrees 2Θ (±0.1 degrees 2Θ),wherein said X-ray powder diffraction pattern is made using CuK_(α1)radiation.

In particular said X-ray powder diffraction pattern comprises peaks at4.99, 20.28, 21.14, 21.64 and 23.23 degrees 2Θ (±0.1 degrees 2Θ),wherein said X-ray powder diffraction pattern is made using CuK_(α1)radiation.

More specifically said X-ray powder diffraction pattern comprises peaksat 4.99, 17.61, 17.77, 20.28, 21.14, 21.64, 23.23 and 27.66 degrees 2Θ(±0.1 degrees 2Θ), wherein said X-ray powder diffraction pattern is madeusing CuK_(α1) radiation.

Even more specifically said X-ray powder diffraction pattern comprisespeaks at 4.99, 15.12, 17.61, 17.77, 18.17, 20.28, 21.14, 21.64, 23.23and 27.66 degrees 2Θ (±0.1 degrees 2Θ), wherein said X-ray powderdiffraction pattern is made using CuK_(α1) radiation.

Even more specifically, the crystalline complex of compound A andL-proline is characterized by an X-ray powder diffraction pattern, madeusing CuK_(α1) radiation, which comprises peaks at degrees 2Θ (±0.1degrees 2Θ) as contained in Table 1.

TABLE 1 X-ray powder diffraction pattern of the crystalline complex ofcompound A and L-proline (only peaks up to 30° in 2 Θ are listed): 2 Θ[°] d-value [Å] Intensity I/I₀ [%] 4.99 17.68 39 7.01 12.61 6 8.25 10.7011 9.95 8.88 12 13.15 6.73 30 13.33 6.64 10 14.08 6.28 4 15.12 5.85 3216.40 5.40 12 16.49 5.37 13 17.11 5.18 6 17.61 5.03 32 17.77 4.99 3518.17 4.88 32 18.32 4.84 28 18.72 4.74 8 19.16 4.63 30 19.96 4.45 2620.28 4.37 56 20.60 4.31 7 21.14 4.20 84 21.64 4.10 100 22.33 3.98 1523.23 3.83 41 24.06 3.70 4 24.51 3.63 15 24.93 3.57 26 25.89 3.44 2326.21 3.40 11 26.84 3.32 8 27.66 3.22 38 27.96 3.19 9 28.26 3.16 5 28.443.14 6 28.75 3.10 6 29.18 3.06 19

Even more specifically, said crystalline complex is characterized by anX-ray powder diffraction pattern, made using CuK_(α1) radiation, whichcomprises peaks at degrees 2Θ (±0.1 degrees 2Θ as shown in [0202].

Furthermore said crystalline complex of the compound A with L-proline ischaracterized by a melting point of above 89° C., in particular in arange from about 89° C. to about 115° C., more preferably in a rangefrom about 89° C. to about 110° C. (determined via DSC; evaluated asonset-temperature; heating rate 10 K/min). It can be observed that thiscrystalline complex melts under dehydration. The obtained DSC curve isshown in [0203].

Said crystalline complex of the compound A with L-proline shows a weightloss by thermal gravimetry (TG). The observed weight loss indicates thatthe crystalline form contains water which may be bound by adsorptionand/or may be part of the crystalline lattice, i.e., the crystallineform may be present as a crystalline hydrate. The content of water inthe crystalline form lies in the range from 0 to about 10 weight-%, inparticular 0 to about 5 weight-%, even more preferably from about 1.5 toabout 5 weight-%. The dotted line depicts a weight loss of between 2.8and 3.8% of water. From the observed weight loss a stoichiometry closeto a monohydrate can be estimated.

Said crystalline complex has advantageous physicochemical propertieswhich are beneficial in the preparation of a pharmaceutical composition.In particular the crystalline complex has a high physical and chemicalstability under various environmental conditions and during theproduction of a medicament. For example the crystals can be obtained ina shape and particle size which are particular suitable in a productionmethod for solid pharmaceutical formulations. In addition the crystalsshow a high mechanical stability that allows grinding of the crystals.Furthermore the crystalline complex does not show a high tendency toabsorb moisture and is chemically stable, i.e., the crystalline complexallows the production of a solid pharmaceutical formulation with a longshelf life. On the other hand the crystalline complex has a favorablyhigh solubility over a wide pH-range which is advantageous in solidpharmaceutical formulations for oral administration.

The X-ray powder diffraction patterns may be recorded using a STOE-STADIP-diffractometer in transmission mode fitted with a location-sensitivedetector (OED) and a Cu-anode as X-ray source (CuK_(α1) radiation,λ=1.54056 Å, 40 kV, 40 mA). In Table 1 the values “2Θ[°]” denote theangle of diffraction in degrees and the values “d [Å]” denote thespecified distances in Å between the lattice planes. The intensity shownin [0202] is given in units of cps (counts per second).

In order to allow for experimental error, the above described 2 Θ valuesshould be considered accurate to ±0.1 degrees 2 Θ, in particular ±0.05degrees 2 Θ. That is to say, when assessing whether a given sample ofcrystals of the compound A is the crystalline form in accordance withthe above described 2 Θ values, a 2 Θ value which is experimentallyobserved for the sample should be considered identical with acharacteristic value described above if it falls within ±0.1 degrees 2 Θof the characteristic value, in particular if it falls within ±0.05degrees 2 Θ of the characteristic value.

The melting point is determined by DSC (Differential Scanningcalorimetry) using a DSC 821 (Mettler Toledo). The weight loss isdetermined by thermal gravimetry (TG) using a TGA 851 (Mettler Toledo).

Also disclosed herein is a method for making a crystalline complex asdefined hereinbefore and hereinafter, said method comprising thefollowing steps:

-   -   a. preparing a solution of one or more SGLT2 inhibitors as        described herein (e.g. compound A or another SGLT2 inhibitor        described herein) and the one or more natural amino acids in a        solvent or a mixture of solvents;    -   b. storing the solution to precipitate the crystalline complex        out of solution;    -   c. removing the precipitate from the solution; and    -   d. drying the precipitate optionally until any excess of said        solvent or mixture of solvents has been removed.

According to step (a) a solution of the one or more SGLT2 inhibitors(e.g., compound A or another SGLT2 inhibitor described herein) and theone or more natural amino acids in a solvent or a mixture of solvents isprepared. Preferably the solution is saturated or at least nearlysaturated or even supersaturated with respect to the crystallinecomplex. In the step (a) the one or more SGLT2 inhibitors may bedissolved in a solution comprising the one or more natural amino acidsor the one or more natural amino acids may be dissolved in a solutioncomprising the SGLT2 inhibitor. According to an alternative procedurethe one or more SGLT2 inhibitors is dissolved in a solvent or mixture ofsolvents to yield a first solution and the one or more natural aminoacids are dissolved in a solvent or mixture of solvents to yield asecond solution. Thereafter said first solution and said second solutionare combined to form the solution according to step (a).

Preferably the molar ratio of the natural amino acid and the one or moreSGLT2 inhibitors (e.g., compound A or any other SGLT2 inhibitordescribed herein) in the solution corresponds to the molar ratio of thenatural amino acid and the one or more SGLT2 inhibitors in thecrystalline complex to be obtained. Therefore a preferred molar ratio isin the range from about 1:2 to 3:1; most preferably about 1:1.

Suitable solvents are preferably selected from the group consisting ofC₁₋₄-alkanols, water, ethyl acetate, acetonitrile, acetone, diethylether, tetrahydrofuran, and mixture of two or more of these solvents.

More preferred solvents are selected from the group consisting ofmethanol, ethanol, isopropanol, water and mixture of two or more ofthese solvents, in particular mixtures of one or more of said organicsolvents with water.

Particularly preferred solvents are selected from the group consistingof ethanol, isopropanol, water and mixtures of ethanol and/orisopropanol with water.

In case a mixture of water and one or more C₁₋₄-alkanols, in particularof methanol, ethanol and/or isopropanol, most preferably of ethanol, istaken, a preferred volume ratio of water:the alkanol is in the rangefrom about 99:1 to 1:99; more preferably from about 50:1 to 1:80; evenmore preferably from about 10:1 to 1:60.

Preferably the step (a) is carried out at about room temperature (about20° C.) or at an elevated temperature up to about the boiling point ofthe solvent or mixture of solvents used.

According to a preferred embodiment the starting material of the one ormore SGLT2 inhibitors (e.g., compound A or any other SGLT2 inhibitordescribed herein) and/or of the one or more natural amino acids and/orof the solvent and mixtures of solvents contain an amount of H₂O whichis at least the quantity required to form a hydrate of the SGLT2inhibitor; in particular at least 1 mol, preferably at least 1.5 mol ofwater per mol of SGLT2 inhibitor. Even more preferably the amount ofwater is at least 2 mol of water per mol of SGLT2 inhibitor. This meansthat either the one or more SGLT2 inhibitors (e.g., compound A) asstarting material or the one or more natural amino acids or said solventor mixture of solvents, or said compounds and/or solvents in combinationcontain an amount of H₂O as specified above. For example if the startingmaterial of the one or more SGLT2 inhibitors (e.g., compound A) or ofthe natural amino acid in step (a) does contain sufficient water asspecified above, a water content of the solvent(s) is not mandatory.

In order to reduce the solubility of the crystalline complex accordingto this invention in the solution, in step (a) and/or in step (b) one ormore antisolvents may be added, preferably during step (a) or at thebeginning of step (b). Water is an example of a suitable antisolvent.The amount of antisolvent is preferably chosen to obtain asupersaturated or saturated solution with respect to the crystallinecomplex.

In step (b) the solution is stored for a time sufficient to obtain aprecipitate, i.e., the crystalline complex. The temperature of thesolution in step (b) is about the same as or lower than in step (a).During storage the temperature of the solution is preferably lowered,preferably to a temperature in the range of 20° C. to 0° C. or evenlower. The step (b) can be carried out with or without stirring. Asknown to the one skilled in the art by the period of time and thedifference of temperature in step (b) the size, shape and quality of theobtained crystals can be controlled. Furthermore the crystallization maybe induced by methods as known in the art, for example by mechanicalmeans such as scratching or rubbing the contact surface of the reactionvessel for example with a glass rod. Optionally the (nearly) saturatedor supersaturated solution may be inoculated with seed crystals.

In step (c) the solvent(s) can be removed from the precipitate by knownmethods as for example by filtration, suction filtration, decantation orcentrifugation.

In step (d) an excess of the solvent(s) is removed from the precipitateby methods known to the one skilled in the art as for example byreducing the partial pressure of the solvent(s), preferably in vacuum,and/or by heating above ca. 20° C., preferably in a temperature rangebelow 100° C., even more preferably below 85° C.

Compound A may be synthesized by methods as specifically and/orgenerally described or cited in international application WO2007/128749(ref. 18) which in its entirety is incorporated herein by reference,and/or in the Examples disclosed herein below. Biological properties ofthe compound A may also be investigated as is described in WO2007/128749(ref. 18).

A crystalline complex as described herein is preferably employed as drugactive substance in substantially pure form, that is to say, essentiallyfree of other crystalline forms of the one or more SGLT2 inhibitors(e.g., compound A). Nevertheless, the invention also embraces acrystalline complex in admixture with another crystalline form or forms.Should the drug active substance be a mixture of crystalline forms, itis preferred that the substance comprises at least 50%-weight, even morepreferably at least 90%-weight, most preferably at least 95%-weight ofthe crystalline complex as described herein.

In view of its ability to inhibit SGLT activity, a crystalline complexaccording to the invention is suitable for the use in the treatmentand/or preventive treatment of conditions or diseases which may beaffected by the inhibition of SGLT activity, particularly SGLT-2activity, in particular the metabolic disorders as described herein. Thecrystalline complex according to the invention is also suitable for thepreparation of pharmaceutical compositions for the treatment and/orpreventive treatment of conditions or diseases which may be affected bythe inhibition of SGLT activity, particularly SGLT-2 activity, inparticular metabolic disorders as described herein. A crystallinecomplex as described herein (in particular of compound A with a naturalamino acid, e.g., proline, particularly L-proline) is also suitable forthe use in the treatment of equine.

Pharmaceutical Compositions and Formulations

SGLT2 inhibitors for use according to the invention may be prepared aspharmaceutical compositions. They may be prepared as solid or as liquidformulations. In either case, they are preferably prepared for oraladministration, preferably in liquid form for oral administration. TheSGLT2 inhibitors may, however, also be prepared, e.g., for parenteraladministration.

Solid formulations include tablets, granular forms, and other solidforms such as suppositories. Among solid formulations, tablets andgranular forms are preferred.

Pharmaceutical compositions within the meaning of the present inventionmay comprise one or more SGLT2 inhibitors according to the presentinvention and one or more excipients. Any excipient that allows for, orsupports, the intended medical effect may be used. Such excipients areavailable to the skilled person. Useful excipients are for exampleanti-adherents (used to reduce the adhesion between the powder(granules) and the punch faces and thus prevent sticking to tabletpunches), binders (solution binders or dry binders that hold theingredients together), coatings (to protect tablet ingredients fromdeterioration by moisture in the air and make large orunpleasant-tasting tablets easier to swallow), disintegrants (to allowthe tablet to break upon dilution), fillers, diluents, flavors, colors,glidants (flow regulators—to promote powder flow by reducinginterparticle friction and cohesion), lubricants (to prevent ingredientsfrom clumping together and from sticking to the tablet punches orcapsule filling machine), preservatives, sorbents, sweeteners, etc.

Formulations according to the invention, e.g., solid formulations, maycomprise carriers and/or disintegrants selected from the group of sugarsand sugar alcohols, e.g., mannitol, lactose, starch, cellulose,microcrystalline cellulose and cellulose derivatives, e. g.,methylcellulose, and the like.

Manufacturing procedures for formulations suitable for equine animalsare known to the person skilled in the art, and for solid formulationscomprise, e.g., direct compression, dry granulation and wet granulation.In the direct compression process, the active ingredient and all otherexcipients are placed together in a compression apparatus that isdirectly applied to press tablets out of this material. The resultingtablets can optionally be coated afterwards in order to protect themphysically and/or chemically, e.g., by a material known from the stateof the art.

A unit for administration, e.g., a single liquid dose or a unit of asolid formulation, e.g., a tablet, may comprise 5 to 2500 mg, or e.g. 5to 2000 mg, 5 mg to 1500 mg, 10 mg to 1500 mg, 10 mg to 1000 mg, or10-500 mg of one or more SGLT2 inhibitors for use according to theinvention. As the skilled person would understand, the content of theone or more SGLT2 inhibitors in a solid formulation, or any formulationas disclosed herein for administration to an equine animal, may beincreased or decreased as appropriate in proportion to the body weightof the equine animal to be treated.

In one embodiment a pharmaceutical composition for use according to theinvention is designed for oral or parenteral administration, preferablyfor oral administration. The oral administration may be ameliorated byexcipients which modify the smell and/or haptic properties of thepharmaceutical composition for the intended patient.

When the one or more SGLT2 inhibitors for use according to the inventionis formulated for oral administration, it is preferred that excipientsconfer properties, e.g., palatability and/or chewability that render theformulation suitable for administration to an equine animal.

Also preferred are liquid formulations. Liquid formulations may be,e.g., solutions, syrups or suspensions. They may be administereddirectly to the equine animal or may be mixed with the food and/or drink(e.g., drinking water, or the like) of the equine animal. One advantageof a liquid formulation (similar to a formulation in granular form), isthat such a dosage form allows precise dosing. For example, the one ormore SGLT2 inhibitors may be dosed precisely in proportion to the bodymass of an equine animal. Typical compositions of liquid formulationsare known to the person skilled in the art.

Dosing and Administration

A practitioner skilled in the art can determine suitable doses for theuses of the present invention. Preferred units dosing units includemg/kg, i.e., mg SGLT2 inhibitor per body mass of the equine animal. Oneor more SGLT2 inhibitors of the invention may, e.g., be administered indoses of 0.01-5 mg/kg bodyweight per day, e.g., 0.01-4 mg/kg, e.g.,0.01-3 mg/kg, e.g., 0.01-2 mg/kg, e.g., 0.01-1.5 mg/kg, e.g., 0.01-1mg/kg, e.g. 0.01-0.75 mg/kg, e.g., 0.01-0.5 mg/kg, e.g., 0.01-0.4 mg/kg,e.g., 0.01-0.4 mg/kg bodyweight per day. Preferably the dose is 0.02-0.5mg/kg bodyweight per day, more preferably 0.03-0.4 mg/kg bodyweight perday, e.g. 0.03-0.3 mg/kg bodyweight per day.

In a preferred embodiment, the one or more SGLT2 inhibitors or apharmaceutically acceptable form thereof may be administered in dosagesof 0.01 to 3.0 mg/kg body weight per day, preferably from 0.02 to 1.0mg/kg body weight per day, more preferably from 0.03 to 0.4 mg/kg bodyweight per day. Thus, the one or more SGLT2 inhibitors orpharmaceutically acceptable form thereof may be prepared for theadministration of 0.01 to 3.0 mg/kg body weight per day, preferably from0.02 to 1.0 mg/kg body weight per day, more preferably from 0.03 to 0.4mg/kg body weight per day.

A practitioner skilled in the art is able to prepare one or more SGLT2inhibitors of the invention for administration according to a desireddose.

Preferably, according to the invention, one or more SGLT2 inhibitors isadministered no more than three times per day, more preferably no morethan twice per day, most preferably only once per day. The frequency ofadministration can be adapted to the typical feeding rate of the equineanimal.

According to the invention, an SGLT2 inhibitor, e.g., compound A, may beadministered such that an appropriate blood plasma concentration of theone or more SGLT2 inhibitors is achieved (e.g., a maximal blood plasmaconcentration, or blood plasma concentration after a given time, e.g.,4, 8, 12 or 24 hours after oral administration, preferably about 8 hoursafter oral administration). E.g., for compound A, the blood plasmaconcentration (e.g., maximal blood plasma concentration or blood plasmaconcentration after said given time after oral administration) may bewithin the range 2 to 4000 nM, e.g. 20 to 3000 nM, or e.g., 40 to 2000nM.

Preferably, following administration and the time required for the oneor more SGLT2 inhibitors to reach the bloodstream, such levels aremaintained in the blood over a time interval of at least 12 hours, morepreferably at least 18 hours, most preferably at least 24 h.

Preferably, according to the invention, one or more SGLT2 inhibitors isadministered orally, in liquid or solid form. The one or more SGLT2inhibitors may be administered directly to the animals mouth (e.g.,using a syringe, preferably a body-weight-graduated syringe) or togetherwith the animal's food or drink (e.g., with its drinking water or thelike), in each case preferably in liquid form. The SGLT2 inhibitors may,however, also be administered, e.g., parenterally, or by any other routeof administration, e.g., rectally.

The one or more SGLT2 inhibitors may be used alone or in combinationwith another drug. In some embodiments, the one or more SGLT2 inhibitorsare used in combination with one or more further oral antihyperglycemicdrugs. When the one or more SGLT2 inhibitors is used in combination witha further drug, the one or more SGLT2 inhibitors and any further drugmay be administered simultaneously, sequentially (in any order), and/oraccording to a chronologically staggered dosage regime. In suchembodiments, when a further drug for combined administration with theone or more SGLT2 inhibitors is not administered simultaneously with theSGLT2 inhibitor, the one or more SGLT2 inhibitors and any further drugare preferably administered within a period of at least 2 weeks, 1month, 2 months, 4 months, 6 months or longer, e.g., 12 months or more.

In some embodiments the one or more SGLT2 inhibitors (whether used aloneor in combination with another drug) is not used in combination with1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[3-(R)-amino-piperidin-1-yl]-xanthineor a pharmaceutically acceptable salt thereof, i.e., the equine animalis not treated with said compound. In some embodiments the one or moreSGLT2 inhibitors is not used in combination with a DPP-IV inhibitor,i.e., the equine animal is not treated with a DPP-IV inhibitor.

In some embodiments, the one or more SGLT2 inhibitors are used as amonotherapy, i.e., stand-alone therapy, i.e., no other medication isadministered to the equine animal for the treatment or prevention of thesame metabolic disorder, i.e., the metabolic disorder for which the oneor more SGLT2 inhibitors is administered. E.g., no other medication isadministered to the equine animal for the treatment or prevention of thesame metabolic disorder within a period of at least 2, 3, or 4 weeksbefore and after administration of the SGLT2 inhibitor.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows that doses of 0.3 mg/kg bodyweight or 3 mg/kg bodyweightorally, or 1 mg/kg bodyweight i.v. of compound A, all caused prominentincreases of urinary glucose concentration in horses.

FIG. 2 shows the correlation between compound A plasma level and urinaryglucose excretion normalized to urinary creatinine (glucose/creatinine).

FIG. 3 compares relative changes in blood glucose over a period of 0-210minutes (mean values; baseline as covariate) in an oral sugar test (OST)in treated and control animals on day 28 of the treatment period (boldlines) with the same animals on day −14 before the beginning of thetreatment period (dotted lines). For comparison the fine dotted linesdepicts the time course of the glucose excursion in the OST of a healthyglucose tolerant horse.

FIG. 4 shows the change of plasma glucose [mM] during a time coursesafter treatment with compound A or its vehicle and feeding. For thecontrol group individual data are given, whereas for horses treated withcompound A mean data are given for each dosing group (0.3 mg/kgbodyweight or 3 mg/kg bodyweight orally, or 1 mg/kg bodyweight i.v.).

FIG. 5 shows a time course of blood insulin concentrations [μIU/mL] ininsulin resistant horses during an OST after 4 weeks of treatment withcompound A (solid lines) or its vehicle (dotted lines). Mean groupvalues are given. Bold line: 2 hours after compound/vehicleadministration; thinner line: 24 hours after last compound/vehicleadministration.

FIG. 6 shows basal plasma insulin levels [μIU/mL] before treatment (day−12), on day 14 and on day 29 of treatment with compound A or itsvehicle. Individual data (thin lines) and the group mean values (boldlines) are given.

FIG. 7 shows the basal insulin sensitivity of treated and control horsesas expressed by the QUICKI (quantitative insulin sensitivity checkindex, i.e., 1/(log(fasting insulin pmol/L)+log(fasting glucosemmol/L)). Measurements were taken before treatment (day −12), on day 14and on day 29 of treatment with compound A or its vehicle. Individualdata (thin lines) and the group mean values (bold lines) are given.

FIG. 8 shows plasma insulin AUC (area under curve) values [μIU/mL/min](baseline as covariate) before treatment (day −12), on day 28 (2 hoursafter compound/vehicle administration) and on day 30 (24 hours afterlast compound/vehicle administration) of treatment with compound A orits vehicle. Individual data (thin lines) and the group mean values(bold lines) are given.

FIG. 9 shows the insulin sensitivity of treated and control horses asexpressed by the Belfiore insulin sensitivity index (i.e.,1/(log(AUCΔinsulin×AUCΔ, glucose)). Measurements were taken beforetreatment (day −12), on day 28 (2 hours after compound/vehicleadministration) and on day 30 (24 hours after last compound/vehicleadministration) of treatment with compound A or its vehicle. Individualdata (thin lines) and the group mean values (bold lines) are given.

FIG. 10A shows the time course of the elimination of non-esterifiedfatty acids (NEFAs, μEq/L) from the bloodstream as measured during anintravenous insulin tolerance test (ivITT) prior to the treatmentperiod. Mean group values are given of the horses treated with compoundA (solid lines) or its vehicle (dotted lines).

FIG. 10B shows the time course of the elimination of non-esterifiedfatty acids (NEFAs, μEq/L) from the bloodstream as measured during anintravenous insulin tolerance test (ivITT) and represent the resultsafter 5 weeks of treatment. Mean group values are given of the horsestreated with compound A (solid lines) or its vehicle (dotted lines).

FIG. 11 shows the basal plasma leptin levels [ng/mL] before treatment(day −12), on day 14 and on day 29 of treatment with compound A or itsvehicle. Individual data (thin lines) and the group mean values (boldlines) are given.

FIG. 12 shows the horses body mass [kg] before treatment (day −12), onday 14 and on day 29 of treatment with compound A or its vehicle.Individual data (thin lines) and the group mean values (bold lines) aregiven.

FIG. 13 shows an X-ray powder diffraction pattern of a representativebatch of a crystalline complex of compound A with L-proline (1:1).

FIG. 14 shows a DSC/TG diagram of a representative batch of acrystalline complex of compound A with L-proline (1:1).

FIGS. 15A and 15B show the increase of plasma glucose [mM] and insulin[μIU/mL] during a glucose challenge, the delta of time “0”—before thechallenge and 120 min after the challenge is given. Open columnsrepresent the values before (“pre”) treatment; filled columns give thevalues on day 14 of treatment (“post”) with compound A (panel A) orplacebo (panel B).

FIG. 16A shows relative changes (group mean values; baseline ascovariate) of blood glucose over a period of 0-240 minutes relative tothe morning feeding on day 2 of the dietary challenge. Bold lines:horses treated with compound A (n=3), dotted lines: untreated controls(n=8).

FIG. 16B shows relative changes (group mean values; baseline ascovariate) of insulin levels over a period of 0-240 minutes relative tothe morning feeding on day 2 of the dietary challenge. Bold lines:horses treated with compound A (n=3), dotted lines: untreated controls(n=8).

EXAMPLES

The following examples show the beneficial therapeutic effects onglycemic control and/or insulin resistance, etc., of using of SGLT2inhibitors in equine animals, according to the present invention. Theseexamples are intended to illustrate the invention in more detail withoutany limitation of the scope of the claims.

Example 1: Pharmacokinetics (PK)/Pharmacodynamics (PD) of Compound ASingle Oral Dosing in Horses

Compound A was administered to overnight fasted horses. The groups (n=3per group) received a single oral or intravenous (i.v.) administrationof either vehicle alone (purified water, macrogol 15 hydroxystearate) orvehicle containing the one or more SGLT2 inhibitors at a dose of 0.3mg/kg bodyweight and 3 mg/kg bodyweight orally and 1 mg/kg bodyweighti.v. PK/PD measurements were taken until day 3 after a singleadministration of compound A or its vehicle.

TABLE 2 Pharmacokinetic data, single dose 1 mg/kg 0.3 mg/kg 3.0 mg/kgParameter i.v. p.o. p.o. _(tmax) [hour] mean 2 1 C_(max) [nmol/L] mean353 3867 AUC_(0→∞) [nmol · h/l] mean 41251 2869 29752 T_(1/2) [hour]mean 7.9 8.5 8.2

Pharmacodynamic Data:

-   -   A prominent increase of urinary glucose concentration was        evident at all doses already 1 hour after administration (mean        group values: controls 0.6 mmol/L; 1 mg/kg i.v.-253 mmol/L; 0.3        mg/kg po-103 mmol/L; 3 mg/kg po-217 mmol/L) and was persistent        for more than 24 hours (see [0189]).    -   None of the doses of compound A altered the basal blood glucose        level in horses as compared to normal reference values.    -   None of the doses of compound A altered the renal function of        horses.

Urinary glucose excretion increase is clearly plasma compound exposuredependent, as shown in [0190].

Example 2. The Effect of Compound A on Urinary and Blood Glucose as Wellas Glucose Tolerance after Repeated Dosing in Horses

Compound A was administered to freely fed normoglycemic,hyperinsulinemic, insulin resistant, obese horses, which exhibit animpaired glucose tolerance. The groups (n=4 per group) received a oncedaily oral administration of either vehicle alone (purified water,macrogol 15 hydroxystearate-0.2 mL/100 kg and approximately 35 mL ofapple sauce) or vehicle containing the one or more SGLT2 inhibitors inincreasing doses up to 1 mg/kg bodyweight for 4 weeks. The treatedhorses received a daily dose of compound A at 0.1 mg/kg bodyweight forthe first 7 days, followed by 0.2 mg/kg bodyweight, from day 20 the dosewas increased to 1 mg/kg bodyweight. Urinary glucose and blood glucosewere measured. Additionally, to evaluate the glucose tolerance, bloodglucose was measured during an oral sugar test (OST, corn syrup 0.15mL/kg) was performed. Blood was collected via jugular vein catheters.Blood samples were taken prior and at 60, 90, 120, 150, 180, and 210 minrelative to sugar application.

-   -   The urinary glucose concentration was significantly elevated by        the treatment—controls<1 mmol/L; treated—˜300 mmol/L.    -   Basal blood glucose levels remained within normal ranges in all        horses throughout the study. No hypoglycemia was observed.

FIG. 3 shows blood glucose levels over a period of 0-210 minutes in anoral sugar test (OST) in animals treated with compound A and in controlanimals treated only with vehicle on day 28 of the treatment period.Mean values are shown (n=4 per group).

Comparison of the glucose curves at the end of the study revealed astatistically significant tendency (p=0.066) for a reduction of theglucose AUC in the horses treated with compound A. The plasma glucoseconcentration at 90 minutes after the challenge was significantly(p=0.038) lower in the treated horses.

These data indicate that treated horses experienced a significantimprovement of their glucose tolerance.

Example 3. The Effect of Compound A on Postprandial Blood Glucose inHorses

The following example shows the effect of compound A on postprandialblood glucose in horses. Compound A was administered to overnight fastedhorses. The groups (n=3 per group) received a single oral or i.v.administration of either vehicle alone (purified water, macrogol 15hydroxystearate) or vehicle containing the one or more SGLT2 inhibitorsat a dose of 0.3 mg/kg bodyweight and 3 mg/kg bodyweight orally and 1mg/kg bodyweight i.v. Two hours after compound administration horseswere fed a test meal. The postprandial glycaemia is quantified 2 hoursthereafter and significantly blunted by all doses of compound A, asshown in [0192]. Compound A is thus clearly capable of effectivelyreducing postprandial glucose levels in horses.

The efficacy of SGLT2 inhibition in accordance with the invention in thetreatment of pathological fasting glucose and/or insulin and/or impairedglucose tolerance can be tested using clinical studies. In studies overa shorter or longer period (e.g., 2-4 weeks or 1-2 years) the success ofthe treatment is examined by determining the fasting glucose and insulinvalues and/or the glucose values after a meal or after a loading test(oral glucose tolerance test or food tolerance test after a definedmeal) after the end of the period of therapy for the study and comparingthem with the values before the start of the study and/or with those ofa placebo group. In addition, the fructosamine value can be determinedbefore and after therapy and compared with the initial value and/or theplacebo value. A significant drop in the fasting or non-fasting glucoseand/or insulin and/or fructosamine levels demonstrates the efficacy ofthe treatment.

Example 4. Effect Upon Insulin Sensitivity and Plasma Insulin Levels inHorses

The following example shows the beneficial effect of compound A ininsulin resistant obese horses. Compound A was administered to freelyfed normoglycemic, obese horses. The groups (n=4 per group) received aonce daily oral administration of either vehicle alone (purified water,macrogol 15 hydroxystearate-0.2 mL/100 kg and approximately 35 mL ofapple sauce) or vehicle containing the one or more SGLT2 inhibitors inincreasing doses up to 1 mg/kg bodyweight for 4 weeks. The followingexperiment was performed prior to treatment, and at the end of the 4week treatment period. The treated horses received a daily dose ofcompound A at 0.1 mg/kg bodyweight for the first 7 days, followed by 0.2mg/kg bodyweight, until day 20 from thereon until the end of the studythe dose was increased to 1 mg/kg bodyweight. At days 28 and 30 thefollowing experiment was performed twice, once approximately 2 h andanother time approximately 24 h after the last administration ofcompound A or its vehicle.

An oral sugar test (OST, corn syrup 0.15 mL/kg) was performed. Blood wascollected via jugular vein catheters. Blood samples were taken prior andat 60, 90, 120, 150, 180, and 210 min relative to sugar application.Glucose and insulin excursions were quantified by calculating thebaseline corrected glucose AUC.

The significance of differences of means between groups was evaluated byrepeated-measures two-factor (time & treatment) ANOVA and post hocmultiple comparisons versus control or the respective baseline readings.

The baseline corrected glucose excursion during the OST did not changeduring the study period or by the treatment. The insulin excursion incontrol horses was not altered throughout the study period but wassignificantly reduced in treated horses as compared to pretreatment orcontrol horses (p<0.05, see FIG. 8). [0193] shows a time course of bloodinsulin concentrations [μIU/mL] in the insulin resistant obese horsesduring an OST after 4 weeks of treatment with compound A or its vehicle.

Plasma insulin levels significantly decreased over the four-weektreatment period in horses treated with compound A, but remainedessentially unchanged on average in control horses given vehicle only(see [0194]).

Insulin sensitivity was significantly increased in treated horses ascompared to pretreatment values. This was demonstrated by determiningbasal insulin sensitivity values as expressed by the QUICKY index(1/log(gluc*ins) and during the challenge (OST) by the modified Belfioreindex (1/log(ΔAUC gluc*ΔAUC ins). As shown in [0195] and in [0197], inthe course of the four-week treatment period, insulin sensitivitysignificantly increased in treated horses, but remained essentiallyunchanged in control horses given vehicle only.

These data indicate that the insulin resistance was significantlyimproved after a 2 to 4 week treatment with compound A.

Example 5. Effect Upon Dyslipidemia, Dysadipokinemia and BodyWeight/Obesitas in Horses

The following example shows the beneficial effect of compound A ininsulin resistant obese horses. The details of the experiments aredescribed in example 4.

To test the effect of compound A treatment on blood lipidhandling/elimination, an intravenous insulin tolerance test (ivITT, 0.03U insulin per kg body mass) was performed prior to start of and on day35 of the treatment period. The test was performed prior to the morningfeeding and approximately 24 hours after the last administration ofcompound A or its vehicle (day 35 only). Blood was collected prior toand at 15, 30, 60, 90, 120 and 150 minutes after the insulin challenge.[0198] shows a time course of baseline corrected blood NEFAconcentrations [μEq/L] in the insulin resistant obese horses during anivITT.

The baseline corrected NEFA elimination curve during the ITT was clearlynot different between the groups prior to treatment (see FIG. 10, panelA). At the end of the treatment period NEFA elimination wassignificantly improved by the compound A treatment (see FIG. 10, panelB).

The use of one or more SGLT2 inhibitors according to the presentinvention advantageously also reduced blood leptin levels. As shown inFIG. 11, in the course of the four-week treatment period, plasma leptinconcentrations significantly decreased in treated horses, but remainedessentially unchanged in control horses given vehicle only.

Additionally, the use of one or more SGLT2 inhibitors according to thepresent invention also reduced significantly the body weight of obesehorses treated with compound A (see FIG. 12) in the course of thefour-week treatment period.

These data indicate that after a 2 to 5 week treatment with compound Aobese, insulin resistant horses showed significantly improved handlingof blood lipids (elimination after a challenge) and an improvedadipokine profile with reduced blood leptin concentrations.Additionally, the body weight was significantly reduced by treatmentwith compound A and indicates the potential to influence obesity and/orregional adiposity in horses.

The efficacy of SGLT2 inhibition in accordance with the invention in thetreatment of pathological obesity and/or regional adiposity can betested using clinical studies. In studies over a shorter or longerperiod (e.g., 3-6 months or 1-2 years) the success of the treatment isexamined by determining e.g., body weight, body condition scores, othermorphometric measurements or non-invasive body composition determinationmethods, e.g., ultrasound determination of fat pad dimension ordeuterium oxide dilution (heavy water) methods. A significant differencein these values during or at the end of the study, compared with theinitial value or compared with a placebo group, or a group given adifferent therapy, proves the efficacy of a pharmaceutical compositionaccording to the invention in the reduction of obesitas and/or regionaladipositas.

Example 6. Effects on Parameters of Inflammation

In studies in horses with metabolic disorders according to the presentinvention running for different lengths of time (e.g., 2 weeks to 12months) the effect of the treatment with SGLT2 inhibitors according tothe invention on inflammation (be it subclinical inflammation, systemicinflammation, low grade systemic inflammation) is evaluated bydetermining in the blood stream for example the concentration ofproinflammatory cytokines (e.g., TNF-alpha or IL-6) or acute phaseproteins (e.g., serum amyloid A or haptoglobulin). A significant fall inthese values during or at the end of the study, compared with theinitial value or compared with a placebo group, or a group given adifferent therapy, proves the efficacy of a pharmaceutical compositionaccording to the invention in the reduction of parameters ofinflammation in horses with metabolic disorders.

Example 7. Effects on Equine Metabolic Syndrome and Associated Diseasesas Laminitis

In studies in horses with metabolic disorders according to the presentinvention, particularly in studies in horses with equine metabolicsyndrome and/or pituitary pars intermedia dysfunction and associateddiseases as laminitis running for different lengths of time (e.g., 2weeks to 12 months) e.g., the success of the improvement in insulinresistance can be checked using the measurement of baseline bloodglucose, blood fructosamine and blood insulin level and therecorresponding relation in the individual horse. Also the glucose andinsulin values after a meal or after a loading test (glucose tolerancetest or insulin tolerance test) after or during a period of therapy andcomparing them with the values before the start of the study and/or withthose of a placebo group can be employed. Additionally, the incidence oflaminitis and/or the reduction of lameness and/or time to recovery froma laminitis episode can be evaluated with respect to the initiallameness values and the time course of lameness throughout anobservation period.

Also the comparison with a placebo group or a group given a differenttherapy can prove the efficacy of a pharmaceutical composition accordingto the invention.

Example 8. Effects of Compound A on Insulin Resistance andHyperinsulinemia in Horses Suffering from Equine Pituitary ParsIntermedia Dysfunction (PPID)

The following example shows the beneficial effect of compound A in aninsulin resistant horse with PPID. PPID was diagnosed based on bloodACTH values—normal ACTH being below 30 pg/mL. The respective horseexhibited an ACTH blood concentration of 966 pg/mL, was thus clearlydiagnosed to suffer from PPID.

An in-feed oral glucose challenge test was performed prior to treatmentand at the end of a 4 week treatment period. For this test, oraldextrose powder at 1 g/kg bodyweight was dissolved in 100 ml tap waterand added to 200 g to wheat bran plus lucerne chaff. Blood was collectedvia the jugular vein prior to the challenge and 2 hours thereafter.

The horse received a once daily dose of 0.3 mg/kg of compound Adissolved in purified water, macrogol 15 hydroxystearate. Compound A wasgiven orally with some apple sauce for 4 weeks. Prior to the treatmentthere was a clear evidence of hyperinsulinemia, the basal plasma insulinconcentrations were 19 μIU/mL. Treatment clearly decreased the basalhyperinsulinemia to normal concentrations (4 μIU/mL) and also clearlyreduced the rise of insulin in response to the challenge by 45%. Theblood glucose response was also slightly reduced—in consequence whendetermining the insulin sensitivity values as expressed by the QUICKYindex (1/log(gluc*ins) 4 weeks of treatment increased basal insulinsensitivity to 160% of the prevalue.

The data show that hyperinsulinemia and insulin resistance in horseswith PPID can be significantly improved by treatment with SGLT2inhibitors, e.g., compound A.

Example 9. Effects of Compound A in Horses with Metabolic Disorders andAssociated Diseases as Laminitis

In the following example horses were selected for a clinical study basedon diagnosis of a metabolic disorder, i.e., hyperinsulinemia and/orinsulin resistance. Insulin resistance was determined with an in-feedoral glucose challenge test, as described above in Example 8. Electedhorses underwent a dietary challenge, i.e., the horses were fed a dietcontaining non-structural carbohydrates (NSC) from oats and molasses atan amount of 10-12 g NSC per kg body weight of the horse. The dietarychallenge was stopped at onset of laminitis and the horses were examinedfor lameness at days 10 and 2 and 4 weeks after onset. Clinical orsubclinical laminitis was diagnosed by a score system includingevaluation of weight shifting, response to foot lift, gait at the walkand trot and in circle, as well as response to a hoof tester. Thedietary challenge induced laminitis in around 90% of horses, i.e., outof 8 treatment naive horses 4 developed clinical laminitis and 3subclinical laminitis.

Two horses that were very comparable in their insulin resistance andshowed a similar degree of laminitis (score 3.5 and 4, respectively)were at onset of laminitis randomly assigned to treatment with compoundA or placebo. Compound A or placebo was given with some apple sauce oncedaily orally at a dose of 0.3 mg/kg of compound A dissolved in purifiedwater, macrogol 15 hydroxystearate. In the horse that was treated withcompound A, the laminitis was resolved already at day 10. In contrast,the horse receiving placebo still had a lameness score of 1 on day 10and 2 weeks after onset of laminitis, only at the 4 week examination thehorse was fully lameness free.

Additionally, in-feed oral glucose challenge tests to determine theeffects on insulin resistance were performed. FIG. 15 shows the changein blood glucose and insulin levels in response to the glucose challengebefore the dietary challenge and at day 14 after onset of laminitis. Thetreatment with compound A clearly reduced the rise of insulin inresponse to the challenge by 88% as compared to prevalue. This parallelswith the observation that the treated horse was already free of lamenessat this point, whereas the horse receiving placebo was still scored tobe clinically abnormal.

A different set of insulin resistant horses (n=3) were treated withcompound A for 3 weeks prior to the start and throughout the dietarychallenge as described above. Compound A was given with some apple sauceonce daily orally at a dose of 0.3 mg/kg of compound A dissolved inpurified water, macrogol 15 hydroxystearate. In untreated horses withinsulin resistance the dietary challenge induced a strong and longlasting increase of blood glucose and insulin. FIG. 16 shows the timecourse of blood glucose and insulin levels over a period of 0-240minutes relative to the morning feeding on day 2 of the dietarychallenge. The horses pretreated with compound A clearly profited fromthe treatment in that their glucose and insulin excursions weresignificantly decreased as compared to untreated horses (n=8) (glucosep=0.003; insulin p=0.06). This is also reflected when calculating theinsulin sensitivity as determined in with the relative area under curveby the modified Belfiore index (1/log(ΔAUC gluc*ΔAUC ins). This wassignificantly increased by the treatment with compound A (p=0.01) ascompared to the untreated horses. Basal insulin levels were also reducedby the treatment with Compound A (mean 51 μIU/mL) as compared tountreated horses. Basal insulin levels were also reduced by thetreatment with Compound A (mean 51 μIU/mL) as compared to untreatedhorses (mean 140 μIU/mL), though these values did not reach statisticalsignificance due to low numbers and variability of the data. Thus, aclear beneficial effect of treatment with compound A on glycemic controland insulin resistance could be observed and this parallels with theobservation, that in this subset of horses by day 13 of the dietarychallenge none had developed clinical laminitis.

The data clearly indicate that in horses with metabolic disordersaccording to the present invention, particularly in studies in horseswith insulin resistance associated with equine metabolic syndrome and/orpituitary pars intermedia dysfunction which is associated with clinicalsigns as laminitis the treatment with SGLT2 inhibitors, e.g., compoundA, can improve not only the insulin resistance, but also reduce the timeto recovery from a laminitis episode as well as prevent the developmentof laminitis.

Example 10. Preparation of1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene(Compound A)

In the foregoing and following text, H atoms of hydroxyl groups are notexplicitly shown in every case in structural formulae. The followingexample of synthesis serves to illustrate a method of preparing1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene(compound A). A method of preparing its crystalline complex withL-proline is also described. It is to be regarded only as a possiblemethod described by way of example, without restriction of the scope ofthe invention. The terms “room temperature” and “ambient temperature”are used interchangeably and denote temperatures of about 20° C. Thefollowing abbreviations are used:

DMF dimethylformamideNMP N-methyl-2-pyrrolidoneTHF tetrahydrofuran

Preparation of 4-bromo-3-hydroxymethyl-1-iodo-benzene

Oxalyl chloride (13.0 mL) is added to an ice-cold solution of2-bromo-5-iodo-benzoic acid (49.5 g) in CH₂Cl₂ (200 mL). DMF (0.2 mL) isadded and the solution is stirred at room temperature for 6 hours. Then,the solution is concentrated under reduced pressure and the residue isdissolved in THF (100 mL). The resulting solution is cooled in anice-bath and LiBH₄ (3.4 g) is added in portions. The cooling bath isremoved and the mixture is stirred at room temperature for 1 hour. Thereaction mixture is diluted with THF and treated with 0.1 M hydrochloricacid. Then, the organic layer is separated and the aqueous layer isextracted with ethyl acetate. The combined organic layers are dried(Na₂SO₄) and the solvent is evaporated under reduced pressure to givethe crude product.

Yield: 47.0 g (99% of theory)

Preparation of 4-bromo-3-chloromethyl-1-iodo-benzene

Thionyl chloride (13 mL) is added to a suspension of4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100mL) containing DMF (0.1 mL). The mixture is stirred at ambienttemperature for 3 hours. Then, the solvent and the excess reagent areremoved under reduced pressure. The residue is triturated with methanoland dried.

Yield: 41.0 g (82% of theory)

Preparation of 4-bromo-1-iodo-3-phenoxymethyl-benzene

Phenol (13 g) dissolved in 4 M KOH solution (60 mL) is added to4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in acetone (50mL). NaI (0.5 g) is added and the resulting mixture is stirred at 50° C.overnight. Then, water is added and the resulting mixture is extractedwith ethyl acetate. The combined extracts are dried (Na₂SO₄) and thesolvent is evaporated under reduced pressure. The residue is purified bychromatography on silica gel (cyclohexane/ethyl acetate 19:1).

Yield: 38.0 g (79% of theory)

Preparation of1-bromo-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene

A 2 M solution of iPrMgCl in THF (11 mL) is added to dry LiCl (0.47 g)suspended in THF (11 mL). The mixture is stirred at room temperatureuntil all the LiCl is dissolved. This solution is added dropwise to asolution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) intetrahydrofuran (40 mL) cooled to −60° C. under argon atmosphere. Thesolution is warmed to −40° C. and then2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (10.7 g, 90% pure)in tetrahydrofuran (5 mL) is added. The resulting solution is warmed to−5° C. in the cooling bath and stirred for another 30 min at thistemperature. Aqueous NH₄Cl solution is added and the resultant mixtureis extracted with ethyl acetate. The combined organic extracts are driedover sodium sulfate and the solvent is removed under reduced pressure.The residue is dissolved in methanol (80 mL) and treated with methanesulfonic acid (0.6 mL) to produce the more stable anomer solely. Afterstirring the reaction solution at 35-40° C. overnight, the solution isneutralized with solid NaHCO₃ and the methanol is removed under reducedpressure. The remainder is diluted with aqueous NaHCO₃ solution and theresulting mixture is extracted with ethyl acetate. The combined extractsare dried over sodium sulfate and the solvent is evaporated to yield thecrude product that is submitted to reduction without furtherpurification.

Yield: 7.8 g (93% of theory)

Preparation of1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene

Boron trifluoride diethyletherate (4.9 mL) is added to a solution of1-bromo-4-(1-methoxy-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene (8.7g) and triethylsilane (9.1 mL) in dichloromethane (35 mL) andacetonitrile (50 mL) cooled to −20° C. at such a rate that thetemperature maintains below −10° C. The resultant solution is warmed to0° C. over a period of 1.5 hours and then treated with aqueous sodiumhydrogen carbonate solution. The resulting mixture is stirred for 0.5hours, the organic solvent is removed and the residue is extracted withethyl acetate. The combined organic layers are dried over sodium sulfateand the solvent is removed. The residue is taken up in dichloromethane(50 mL) and pyridine (9.4 mL), acetic anhydride (9.3 mL) and4-dimethylaminopyridine (0.5 g) are added in succession to the solution.The solution is stirred for 1.5 hours at ambient temperature and thendiluted with dichloromethane. This solution is washed twice with 1 Mhydrochloric acid and dried over sodium sulfate. After the solvent isremoved, the residue is recrystallized from ethanol to furnish theproduct as a colorless solid.

Yield: 6.78 g (60% of theory)

Mass spectrum (ESI⁺): m/z=610/612 (Br) [M+NH₄]⁺

Preparation of2-(phenoxymethyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile

A flask charged with zinc cyanide (1.0 g), zinc (30 mg),Pd₂(dibenzylideneacetone)₃*CHCl₃ (141 mg) and tri-tert-butylphosphoniumtetrafluoroborate (111 mg) is flushed with argon. Then a solution of1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene(5.4 g) in NMP (12 mL) is added and the resulting mixture is stirred atroom temperature for 18 hours. After dilution with ethyl acetate, themixture is filtered and the filtrate is washed with aqueous sodiumhydrogen carbonate solution. The organic phase is dried (sodium sulfate)and the solvent is removed. The residue is recrystallized from ethanol.

Yield: 4.10 g (84% of theory)

Mass spectrum (ESI⁺): m/z=557 [M+NH₄]⁺

Alternatively, the compound described above is synthesized starting from1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzeneusing copper(I) cyanide (2 equivalents) in NMP at 210° C.

Preparation of2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile

A 33% solution of hydrobromic acid in acetic acid (15 mL) is added to asolution of2-phenyloxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile(0.71 g) and acetic anhydride (0.12 mL) in acetic acid (10 ml). Theresulting solution is stirred at 55° C. for 6 hours and then cooled inan ice-bath. The reaction mixture is neutralized with chilled aqueouspotassium carbonate solution, and the resultant mixture is extractedwith ethyl acetate. The combined organic extracts are dried over sodiumsulfate and the solvent is removed under reduced pressure. The residueis taken up in ethyl acetate/cyclohexane (1:5), and the precipitate isseparated by filtration and dried at 50° C. to give the pure product.

Yield: 0.52 g (75% of theory)

Mass spectrum (ESI⁺): m/z=543/545 (Br) [M+NH₄]⁺

Preparation of 4-cyclopropyl-phenylboronic acid

2.5 M solution of nButyllithium in hexane (14.5 mL) is added dropwise to1-bromo-4-cyclopropyl-benzene (5.92 g) dissolved in THF (14 mL) andtoluene (50 mL) and chilled to −70° C. The resultant solution is stirredat −70° C. for 30 min before triisopropyl borate (8.5 mL) is added. Thesolution is warmed to −20° C. and then treated with 4 M aqueoushydrochloric acid (15.5 mL). The reaction mixture is further warmed toroom temperature and then the organic phase is separated. The aqueousphase is extracted with ethyl acetate and the combined organic phasesare dried (sodium sulfate). The solvent is evaporated and the residue iswashed with a mixture of ether and cyclohexane to give the product as acolorless solid.

Yield: 2.92 g (60% of theory)

Mass spectrum (ESI⁺): m/z=207 (Cl) [M+HCOO]⁻

Preparation of1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene

An Argon filled flask is charged with2-bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-benzonitrile(1.60 g), 4-cyclopropyl-phenylboronic acid (1.0 g), potassium carbonate(1.85 g) and a degassed 3:1 mixture of acetone and water (22 mL). Themixture is stirred at room temperature for 5 min, before it is cooled inan ice-bath. Then palladium dichloride (30 mg) is added and the reactionmixture is stirred for 16 hours at ambient temperature. The mixture isthen diluted with brine and extracted with ethyl acetate. The combinedextracts are dried over sodium sulfate and the solvent is removed underreduced pressure. The residue is dissolved in methanol (20 mL) andtreated with 4 M aqueous potassium hydroxide solution (4 mL). Theresulting solution is stirred at ambient temperature for 1 hour and thenneutralized with 1 M hydrochloric acid. The methanol is evaporated, andthe residue is diluted with brine and extracted with ethyl acetate. Theorganic extracts collected are dried over sodium sulfate, and thesolvent is removed. The residue is chromatographed on silica gel(dichloromethane/methanol 1:0->8:1).

Yield: 0.91 g (76% of theory)

Mass spectrum (ESI⁺): m/z=413 [M+NH₄]⁺

Preparation of a Crystalline Complex (1:1) of Compound A with L-Proline

L-proline (0.34 g) dissolved in 2.1 mL of a mixture of ethanol and water(volume ratio 10:1) is added to a solution of1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene (1.17g, obtained as described above) dissolved in 2 mL ethanol. The resultingsolution is allowed to stand at ambient temperature. After about 16hours, the crystalline complex is isolated as white crystals byfiltration. If necessary the crystallization may be initiated byscratching with a glass rod or metal spatula for example, or byinoculating with seed crystals. Residual solvent is removed by storingthe crystals at slightly elevated temperature (30 to 50° C.) undervacuum for about 4 hours to yield 1.27 g of the crystalline 1:1 complexof L-proline and1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene.

Several batches of the crystalline complex according to the abovepreparation are obtained. The X-ray powder diffraction patternscoincide. The melting points were determined via DSC and evaluated asonset-temperature. Examples of melting points are approximately 89° C.,90° C., 92° C., 101° C. and 110° C. The X-ray powder diffraction patternas contained in Table 2 and as depicted in [0202] the DSC and TG diagramin [0203] correspond to a batch with a melting point of approximately90° C.

The X-ray powder diffraction pattern of the crystalline complex of thecompound A and L-proline (peaks up to 30° in 2 Θ) is provided above inTable 1.

Example 11. Formulations

Some examples of formulations are described in which the term “activesubstance” denotes one or more SGLT2 inhibitors or pharmaceuticallyacceptable forms thereof, e.g., a prodrug or a crystalline form, for useaccording to the invention. In the case of a combination with one oradditional active substances, the term “active substance” may alsoinclude the additional active substance.

Tablets Containing 100 mg of Active Substance Composition:

1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg

Method of Preparation:

The active substance, lactose and starch are mixed together anduniformly moistened with an aqueous solution of thepolyvinylpyrrolidone. After the moist composition has been screened (2.0mm mesh size) and dried in a rack-type dryer at 50° C. it is screenedagain (1.5 mm mesh size) and the lubricant is added. The finishedmixture is compressed to form tablets.

Weight of tablet: 220 mgDiameter: 10 mm, biplanar, faceted on both sides and notched on oneside.

Tablets Containing 150 mg of Active Substance Composition:

1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mgcorn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0mg magnesium stearate 1.0 mg 300.0 mg

Preparation:

The active substance mixed with lactose, corn starch and silica ismoistened with a 20% aqueous polyvinylpyrrolidone solution and passedthrough a screen with a mesh size of 1.5 mm. The granules, dried at 45°C., are passed through the same screen again and mixed with thespecified amount of magnesium stearate. Tablets are pressed from themixture.

Weight of tablet: 300 mg

die: 10 mm, flat

Hard Gelatin Capsules Containing 150 mg of Active Substance Composition:

1 capsule contains: active substance 150.0 mg corn starch (dried)approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate3.0 mg approx. 420.0 mg

Preparation:

The active substance is mixed with the excipients, passed through ascreen with a mesh size of 0.75 mm and homogeneously mixed using asuitable apparatus. The finished mixture is packed into size 1 hardgelatin capsules.

Capsule filling: approx. 320 mg

Capsule shell: size 1 hard gelatin capsule.

Suppositories Containing 150 mg of Active Substance Composition:

1 suppository contains: active substance 150.0 mg polyethylene glycol1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitanmonostearate 840.0 mg 2,000.0 mg

Preparation:

After the suppository mass has been melted the active substance ishomogeneously distributed therein and the melt is poured into chilledmolds.

Ampoules Containing 10 mg Active Substance Composition:

active substance 10.0 mg 0.01N hydrochloric acid/NaCl q.s.double-distilled water ad 2.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 2ml ampoules.

Ampoules Containing 50 mg of Active Substance Composition:

active substance 50.0 mg 0.01N hydrochloric acid/NaCl q.s.double-distilled water ad 10.0 ml

Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl,made isotonic with common salt, filtered sterile and transferred into 10ml ampoules.

REFERENCES

All references cited herein are incorporated by reference in theirentirety.

-   1) Katz & Bailey (2012) Equine Veterinary Journal 44:752-761-   2) Venugopal et al. (2011) Equine Veterinary Journal 43:744-749-   3) Treiber et al. (2006) The Journal of Nutrition 136 (7    Suppl):20945-20985-   4) Tinworth et al. (2012) The Veterinary Journal 191:79-84-   5) Gehlen (2014) Journal of Equine Veterinary Science 34(4): 508-513-   6) Frank et al. (2011) Journal of Veterinary Internal Medicine    24(3):467-75-   7) WO01/27128-   8) WO03/099836-   9) WO2005/092877-   10) WO2006/034489-   11) WO2006/064033-   12) WO2006/117359-   13) WO2006/117360-   14) WO2007/025943-   15) WO2007/028814-   16) WO2007/031548-   17) WO2007/093610-   18) WO2007/128749-   19) WO2008/049923-   20) WO2008/055870-   21) WO2008/055940-   22) WO2009/022020-   23) WO2009/022008-   24) WO2008/116179-   25) WO2008/002824-   26) WO2005/012326-   27) WO2009/035969-   28) WO2008/069327-   29) WO2006/120208-   30) WO2011/039108-   31) WO2011/039107-   32) WO2004/007517-   33) WO2004/080990-   34) WO2007/114475-   35) WO2007/140191-   36) WO2008/013280-   37) WO2010/023594-   38) EP1213296-   39) EP1354888-   40) EP1344780-   41) EP1489089-   42) WO2008/042688-   43) WO2009/014970-   44) WO2014/016381

1. A method of treating or preventing a metabolic disorder in an equinecomprising administering an SGLT2 inhibitor or pharmaceuticallyacceptable form thereof, wherein the metabolic disorder is one or moredisorders selected from laminitis, vascular dysfunction, hypertension,hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary ParsIntermedia Dysfunction and/or Equine Metabolic Syndrome.
 2. The methodaccording to claim 1, wherein said SGLT2 inhibitor or pharmaceuticallyacceptable form thereof is selected from the group consisting of thefollowing compounds or pharmaceutically acceptable forms thereof: aglucopyranosyl-substituted benzene derivative of the formula (1)

wherein R1 denotes cyano, Cl or methyl; R2 denotes H, methyl, methoxy orhydroxyl; and R3 denotes cyclopropyl, hydrogen, fluorine, chlorine,bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl,cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl,1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy,difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl,ethylsulfinyl, ethyl sulfonyl, trimethylsilyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano,wherein R3 is preferably selected from cyclopropyl, ethyl, ethinyl,ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or aderivative thereof wherein one or more hydroxyl groups of theβ-D-glucopyranosyl group are acylated with groups selected from(C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl andphenyl-(C1-3-alkyl)-carbonyl; Dapagliflozin, represented by formula (3):

Canagliflozin, represented by formula (4):

Empagliflozin, represented by formula (5):

Luseogliflozin, represented by formula (6):

Tofogliflozin, represented by formula (7):

Ipragliflozin, represented by formula (8):

Ertugliflozin, represented by formula (9):

Atigliflozin, represented by formula (10):

Remogliflozin, represented by formula (11):

a thiophene derivative of the formula (12)

wherein R denotes methoxy or trifluoromethoxy;1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene;represented by formula (13);

a spiroketal derivative of the formula (14):

wherein R denotes methoxy, trifluoromethoxy, ethoxy, ethyl, isopropyl ortert. butyl; a pyrazole-O-glucoside derivative of the formula (15)

wherein R1 denotes C1-3-alkoxy, L1, L2 independently of each otherdenote H or F, R6 denotes H, (C1-3-alkyl)carbonyl,(C1-6-alkyl)oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl orbenzylcarbonyl; a compound of the formula (16):

Sergliflozin, represented by formula (17):

a compound represented by formula (18):

wherein R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.
 3. Themethod of claim 2, wherein said SGLT2 inhibitor or pharmaceuticallyacceptable form thereof is selected from the group consisting of thefollowing compounds or pharmaceutically acceptable forms thereof: aglucopyranosyl-substituted benzene derivative of the formula (1)

wherein R1 denotes cyano, Cl or methyl; R2 denotes H, methyl, methoxy orhydroxy; and R3 denotes cyclopropyl, hydrogen, fluorine, chlorine,bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,iso-butyl, tert-butyl, 3-methyl-but-1-yl, cyclobutyl, cyclopentyl,cyclohexyl, 1-hydroxy-cyclopropyl, 1-hydroxy-cyclobutyl,1-hydroxy-cyclopentyl, 1-hydroxy-cyclohexyl, ethinyl, ethoxy,difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxyl-ethyl,hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl,3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl,2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl,2-ethoxy-ethyl, hydroxy, difluoromethyloxy, trifluoromethyloxy,2-methyloxy-ethyloxy, methylsulfanyl, methylsulfinyl, methlysulfonyl,ethylsulfinyl, ethyl sulfonyl, trimethylsilyl,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy or cyano;wherein R3 is preferably selected from cyclopropyl, ethyl, ethinyl,ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or aderivative thereof wherein one or more hydroxyl groups of theβ-D-glucopyranosyl group are acylated with groups selected from(C1-18-alkyl)carbonyl, (C1-18-alkyl)oxycarbonyl, phenylcarbonyl andphenyl-(C1-3-alkyl)-carbonyl. Dapagliflozin, represented by formula (3):

Canagliflozin, represented by formula (4):

Empagliflozin, represented by formula (5):

Ertugliflozin, represented by formula (9):

a compound represented by formula (18):

wherein: R3 is selected from cyclopropyl, ethyl, ethinyl, ethoxy,(R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy.
 4. Themethod according to claim 1, wherein the metabolic disorder is aclinical condition or sign associated with insulin resistance orhyperinsulinaemia.
 5. The method according to claim 1, wherein themetabolic disorder is hyperinsulinemia and/or insulin resistance, andwherein said hyperinsulinemia and/or insulin resistance is associatedwith one or more of laminitis, vascular dysfunction, hypertension,hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary ParsIntermedia Dysfunction and/or Equine Metabolic Syndrome.
 6. The methodaccording to claim 1, wherein the equine animal is a horse or a pony. 7.The method according to claim 1, wherein the equine animal is obeseand/or exhibits regional adiposity.
 8. The method according to claim 1,wherein the composition comprises a crystalline complex of the SGLT2inhibitor or pharmaceutically acceptable form thereof and an amino acid,and the amino acid is proline.
 9. The method according to claim 1,wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereofis administered orally or parenterally.
 10. The method according toclaim 1, wherein the SGLT2 inhibitor or pharmaceutically acceptable formthereof is administered orally.
 11. The method according to claim 1,wherein the SGLT2 inhibitor or pharmaceutically acceptable form thereofis administered in a range of from 0.01 to 5 mg/kg body weight per day.12. The method according to claim 1, wherein the SGLT2 inhibitor orpharmaceutically acceptable form thereof is administered in a range offrom 0.02 to 1.0 mg/kg body weight per day.
 13. The method according toclaim 1, wherein the SGLT2 inhibitor or pharmaceutically acceptable formthereof is administered in a range of from 0.03 to 0.4 mg/kg body weightper day.
 14. The method according to claim 1, wherein the SGLT2inhibitor or pharmaceutically acceptable form thereof is administeredonce per day.
 15. The method according to claim 1, wherein the equineanimal is not obese and/or is present with muscle wasting and/orexhibits hyperglycemia.
 16. The method of claim 1, wherein thecomposition comprises a 1:1:1 crystalline complex of the SGLT2 inhibitoror pharmaceutically acceptable form thereof, L-proline and water in acrystalline form.
 17. The method according to claim 16, wherein the1:1:1 crystalline complex is characterized by an X-ray powderdiffraction pattern that comprises peaks at 20.28, 21.14 and 21.64degrees 2Θ (±0.1 degrees 2θ), wherein said X-ray powder diffractionpattern is made using CuK_(α1) radiation.
 18. The method of claim 1,wherein said laminitis, vascular dysfunction, hypertension, hepaticlipidosis, atherosclerosis, hyperadrenocorticism, Pituitary ParsIntermedia Dysfunction and/or Equine Metabolic Syndrome is associatedwith insulin resistance and/or hyperinsulinemia.